bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2024–11–24
fifty papers selected by
Chun-Chi Chang, Universitäts Spital Zürich
  1. The C3-C3aR axis modulates trained immunity in alveolar macrophages.
  2. Developmental programming of tissue-resident macrophages.
  3. Multiomics reveals age-dependent metabolic reprogramming of macrophages by wound bed niche secreted signals.
  4. Analysis of the potential long-lasting effects of probiotic Debaryomyces hansenii CBS 8339 on trained immunity in newborn goats.
  5. A host-directed adjuvant resuscitates and sensitizes intracellular bacterial persisters to antibiotics.
  6. Methylglyoxal is an antibacterial effector produced by macrophages during infection.
  7. Genetically diverse Mycobacterium tuberculosis isolates manipulate inflammasome activation and IL-1β secretion independently of macrophage metabolic rewiring.
  8. Trained innate immunity in response to nuclear antigens in systemic lupus erythematosus.
  9. Collagen binding adhesin restricts Staphylococcus aureus skin infection.
  10. Galectin-3 disrupts tight junctions of airway epithelial cell monolayers by inducing expression and release of matrix metalloproteinases upon influenza a infection.
  11. The diverse roles of neutrophils from protection to pathogenesis.
  12. Spatiotemporal Clusters of ERK Activity Coordinate Cytokine-induced Inflammatory Responses in Human Airway Epithelial Cells.
  13. Next-generation microbiome therapeutics: why it is important to consider the space left in the wake of antibiotic treatment.
  14. TLR priming licenses NAIP inflammasome activation by immunoevasive ligands.
  15. Liushen Wan alleviates the virulence and inflammation of Staphylococcus aureus via NLRP3 inflammasome and TLR2-NF-κB/p38 MAPK signaling pathways.
  16. Staphylococcus epidermidis alters macrophage polarization and phagocytic uptake by extracellular DNA release in vitro.
  17. The Symbiotic Defence: Lung Microbiota and The Local Immune System.
  18. Efflux pumps: gatekeepers of antibiotic resistance in Staphylococcus aureus biofilms.
  19. Prenatal Skin Cell Atlas reveals macrophages' role beyond immunity.
  20. Cell Growth and Division of Staphylococcus aureus.
  21. Respiratory bioenergetics is enhanced in human, but not bovine macrophages after exposure to M. bovis PPD: Exploratory insights into overall similar Cellular Metabolic Profiles.
  22. A cross-tissue, age-specific flow cytometry reference for immune cells in the airways and blood of children.
  23. Co-culture of human AT2 cells with fibroblasts reveals a MUC5B phenotype: insights from an organoid model.
  24. Polymicrobial interactions between Staphylococcus aureus and Pseudomonas aeruginosa promote biofilm formation and persistence in chronic wound infections.
  25. Targeting SphK1/S1PR3 axis ameliorates sepsis-induced multiple organ injury via orchestration of macrophage polarization and glycolysis.
  26. Interactions between tumor-associated macrophages and regulated cell death: therapeutic implications in immuno-oncology.
  27. A preliminary investigation on the protective effects of β-glucan and mannan induced trained immunity in pufferfish Takifugu obscurus.
  28. Your friends shape your microbiome - and so do their friends.
  29. Ferroptosis Induces gut microbiota and metabolic dysbiosis in Collagen-Induced arthritis mice via PAD4 enzyme.
  30. Perturbations in the airway microbiome are associated with type 2 asthma phenotype and severity.
  31. Cytosolic delivery of innate immune agonists.
  32. Nα-Terminal Acetylation Meets Ferroptosis via N-Degron Pathway.
  33. The Microbiome: From the Beginning to the End.
  34. Human monocyte-derived macrophages shift subcellular metalloprotease activity depending on their activation state.
  35. Erratum for Hassall et al., "Dissecting Individual Interactions between Pathogenic and Commensal Bacteria within a Multispecies Gut Microbial Community".
  36. Gut microbiota in health and disease: advances and future prospects.
  37. ASIC1a regulates airway epithelial cell pyroptosis in acute lung injury by NLRP3-Caspase1-GSDMD pathway.
  38. Disentangling the molecular mystery of tumour-microbiota interactions: Microbial metabolites.
  39. Immunoglobulin A Antibodies: From Protection to Harmful Roles.
  40. The Contribution of the Monocyte-Macrophage Lineage to Immunotherapy Outcomes.
  41. Ferroptosis: mechanisms and therapeutic targets.
  42. Gasdermin D unlocks metabolic pathways to enhance tissue regeneration.
  43. Niche-specific metabolic phenotypes can be used to identify antimicrobial targets in pathogens.
  44. A pan-family screen of nuclear receptors in immunocytes reveals ligand-dependent inflammasome control.
  45. Macrophage modulation of tumor immunity.
  46. Relationships between bacteria and the mucus layer.
  47. PDCD6 regulates lactate metabolism to modulate LC3-associated phagocytosis and antibacterial defense.
  48. Spatially restricted immune and microbiota-driven adaptation of the gut.
  49. Mucosal immunization with the lung Lactobacillus-derived amphiphilic exopolysaccharide adjuvanted recombinant vaccine improved protection against P. aeruginosa infection.
  50. Downregulation of Tight Junction Protein MAGI1 by Interferon-γ Contributes to Barrier Dysfunction in Chronic Rhinosinusitis With Nasal Polyps.
  1. bioRxiv. 2024 Nov 05. pii: 2024.11.01.621042. [Epub ahead of print]
    The C3-C3aR axis modulates trained immunity in alveolar macrophages.
    Alexander P Earhart, Rafael Aponte Alburquerque, Marick Starick, Aasritha Nallapu, Lorena Garnica, Ayse Naz Ozanturk, Rahul Kumar Maurya, Xiaobo Wu, Jeffrey A Haspel, Hrishikesh S Kulkarni.
      Complement protein C3 is crucial for immune responses in mucosal sites such as the lung, where it aids in microbe elimination and enhances inflammation. While trained immunity - enhanced secondary responses of innate immune cells after prior exposure - is well-studied, the role of the complement system in trained immune responses remains unclear. We investigated the role of C3 in trained immunity and found that in vivo, trained wild-type mice showed significantly elevated pro-inflammatory cytokines and increased C3a levels upon a second stimulus, whereas C3-deficient mice exhibited a blunted cytokine response and heightened evidence of lung injury. Ex vivo, C3-deficient alveolar macrophages (AMs) displayed reduced chemokine and cytokine output after training, which was restored by exogenous C3 but not by C3a. Inhibiting C3aR, both pharmacologically and with a genetic C3aR knockout, prevented this restoration, indicating the necessity of C3aR engagement. Mechanistically, trained WT AMs demonstrated enhanced glycolytic activity compared to C3-deficient AMs - a defect corrected by exogenous C3 in a C3aR-dependent manner. These findings reveal that C3 modulates trained immunity in AMs through C3aR signaling, affecting cytokine production and metabolic reprogramming, and highlight a novel role for C3 in trained immunity.
    DOI:  https://doi.org/10.1101/2024.11.01.621042
  2. Front Immunol. 2024 ;15 1475369
    Developmental programming of tissue-resident macrophages.
    Maria Francesca Viola, Eliana Franco Taveras, Elvira Mass.
      Macrophages are integral components of the innate immune system that colonize organs early in development and persist into adulthood through self-renewal. Their fate, whether they are replaced by monocytes or retain their embryonic origin, depends on tissue type and integrity. Macrophages are influenced by their environment, a phenomenon referred to as developmental programming. This influence extends beyond the local tissue microenvironment and includes soluble factors that can reach the macrophage niche. These factors include metabolites, antibodies, growth factors, and cytokines, which may originate from maternal diet, lifestyle, infections, or other developmental triggers and perturbations. These influences can alter macrophage transcriptional, epigenetic, and metabolic profiles, affecting cell-cell communication and tissue integrity. In addition to their crucial role in tissue immunity, macrophages play vital roles in tissue development and homeostasis. Consequently, developmental programming of these long-lived cells can modulate tissue physiology and pathology throughout life. In this review, we discuss the ontogeny of macrophages, the necessity of developmental programming by the niche for macrophage identity and function, and how developmental perturbations can affect the programming of macrophages and their subtissular niches, thereby influencing disease onset and progression in adulthood. Understanding these effects can inform targeted interventions or preventive strategies against diseases. Finally, understanding the consequences of developmental programming will shed light on how maternal health and disease may impact the well-being of future generations.
    Keywords:  developmental programming; hematopoiesis; macrophage; maternal immune activation (MIA); niche
    DOI:  https://doi.org/10.3389/fimmu.2024.1475369
  3. bioRxiv. 2024 Nov 03. pii: 2024.10.30.621159. [Epub ahead of print]
    Multiomics reveals age-dependent metabolic reprogramming of macrophages by wound bed niche secreted signals.
    Maria Fernanda Forni, Gabriela A Pizzurro, Will Krause, Amanda F Alexander, Kate Bridges, Yiting Xu, Olivia Justynski, Anthony Gabry, Niels Olsen Saraiva Camara, Kathryn Miller-Jensen, Valerie Horsley.
      The cellular metabolism of macrophages depends on tissue niches and can control macrophage inflammatory or resolving phenotypes. Yet, the identity of signals within tissue niches that control macrophage metabolism is not well understood. Here, using single-cell RNA sequencing of macrophages in early mouse wounds, we find that, rather than gene expression of canonical inflammatory or resolving polarization markers, metabolic gene expression defines distinct populations of early wound macrophages. Single-cell secretomics and transcriptomics identify inflammatory and resolving cytokines expressed by early wound macrophages, and we show that these signals drive metabolic inputs and mitochondrial metabolism in an age-dependent manner. We show that aging alters the metabolome of early wound macrophages and rewires their metabolism from mitochondria to glycolysis. We further show that macrophage-derived Chi3l3 and IGF-1 can induce metabolic inputs and mitochondrial mass/metabolism in aged and bone marrow-derived macrophages. Together, these findings reveal that macrophage-derived signals drive the mitochondrial metabolism of macrophages within early wounds in an age-dependent manner and have implications for inflammatory diseases, chronic injuries, and age-related inflammatory diseases.
    In Brief: This study reveals that macrophage subsets in early inflammatory stages of skin wound healing are defined by their metabolic profiles rather than polarization phenotype. Using single-cell secretomics, we establish key macrophage cytokines that comprise the in vivo wound niche and drive mitochondrial-based metabolism. Aging significantly alters macrophage heterogeneity and increases glycolytic metabolism, which can be restored to OxPHOS-based metabolism with young niche cytokines. These findings highlight the importance of the tissue niche in driving macrophage phenotypes, with implications for aging-related impairments in wound healing.
    Highlights: Single cell transcriptional analysis reveals that reveals that metabolic gene expression identifies distinct macrophage populations in early skin wounds.Single-cell secretomic data show that young macrophages contribute to the wound bed niche by secreting molecules such as IGF-1 and Chi3l3.Old wound macrophages display altered metabolomics, elevated glycolytic metabolism and glucose uptake, and reduced lipid uptake and mitochondrial mass/metabolism.Chi3l3 but not IGF-1 secretion is altered in macrophages in an age dependent manner.Chi3l3 can restore mitochondrial mass/metabolism in aged macrophages.
    DOI:  https://doi.org/10.1101/2024.10.30.621159
  4. Dev Comp Immunol. 2024 Nov 20. pii: S0145-305X(24)00164-2. [Epub ahead of print] 105292
    Analysis of the potential long-lasting effects of probiotic Debaryomyces hansenii CBS 8339 on trained immunity in newborn goats.
    Miriam Angulo, Carlos Angulo.
      Trained immunity has been described as the memory capacity of the innate immune system. Several microbial components have been shown to induce trained immunity. Research on the potential of probiotics to trigger these effects has been limited to a few in vitro studies but remains completely unknown in vivo. Components from the probiotic Debaryomyces hansenii CBS 8339 (Dh) have been shown to induce innate immune memory in goat kids and calves. In the present study, stimulating innate immune cells from newborn goats with probiotic Dh increased respiratory burst activity and nitric oxide production, while cell phagocytosis was unaffected. Glucose uptake was enhanced in goat's cells stimulated with Dh, but lactate production was decreased. In newborn goats, after the training scheme (via oral probiotic administration), cell phagocytosis, nitric oxide production and glycolysis - through the upregulation of AKT and HIF1A gene expression, glucose consumption and lactate production- were enhanced. The expression of IL1B gene was similar between the D. hansenii and control groups. Moreover, the potential long-lasting effects were assessed 30 days after initiation of the training scheme. Cell phagocytosis, respiratory burst and myeloperoxidase activity were enhanced, while glycolytic parameters remained unaffected. Altogether, the results of the present study suggest that the immune training scheme may induce trained immunity by the probiotic D. hansenii in newborn goats. However, our findings were not conclusive regarding the long-lasting (one-month) effects of trained immunity by probiotics.
    Keywords:  Immunological memory; beneficial microorganisms; caprine; health
    DOI:  https://doi.org/10.1016/j.dci.2024.105292
  5. bioRxiv. 2024 Oct 30. pii: 2024.09.30.615828. [Epub ahead of print]
    A host-directed adjuvant resuscitates and sensitizes intracellular bacterial persisters to antibiotics.
    Kuan-Yi Lu, Xiangbo Yang, Matthew J G Eldridge, Nikki J Wagner, Brian Hardy, Matthew Axtman, Sarah E Rowe, Xiaodong Wang, Vance G Fowler, Sophie Helaine, Kenneth H Pearce, Brian P Conlon.
      There are two major problems in the field of antimicrobial chemotherapy-antibiotic resistance and antibiotic tolerance. In the case of antibiotic tolerance, antibiotics fail to kill the bacteria as their phenotypic state affords them protection from the bactericidal activity of the antibiotic. Antibiotic tolerance can affect an entire bacterial population, or a subset of cells known as persister cells. Interaction with the host induces the formation of persister cells in numerous pathogens, with reactive oxygen and nitrogen species production being heavily implicated in the collapse of bacterial energy levels and entrance into an antibiotic tolerant state. Here, we developed a high-throughput screen to identify energy modulators for intracellular Staphylococcus aureus . The identified compound, KL1 , increases intracellular bacterial energy and sensitizes the persister population to antibiotics, without causing cytotoxicity or bacterial outgrowth. We demonstrate that KL1 exhibits adjuvant activity in a murine model of S. aureus bacteremia and intracellular infection of Salmonella Typhimurium . Transcriptomic analysis and further studies on its mechanism of action reveal that KL1 modulates host immune response genes and suppresses the production of reactive species in host macrophages, alleviating one of the major stressors that induce antibiotic tolerance. Our findings highlight the potential to target intracellular persister cells by stimulating their metabolism and encourage larger efforts to address antibiotic tolerance at the host-pathogen interface, particularly within the intracellular milieu.
    DOI:  https://doi.org/10.1101/2024.09.30.615828
  6. bioRxiv. 2024 Nov 03. pii: 2024.11.03.621721. [Epub ahead of print]
    Methylglyoxal is an antibacterial effector produced by macrophages during infection.
    Andrea Anaya-Sanchez, Samuel B Berry, Scott Espich, Alex Zilinskas, Phuong M Tran, Carolina Agudelo, Helia Samani, K Heran Darwin, Daniel A Portnoy, Sarah A Stanley.
      Infected macrophages transition into aerobic glycolysis, a metabolic program crucial for control of bacterial infection. However, antimicrobial mechanisms supported by aerobic glycolysis are unclear. Methylglyoxal is a highly toxic aldehyde that modifies proteins and DNA and is produced as a side-product of glycolysis. Here we show that despite the toxicity of this aldehyde, infected macrophages generate high levels of methylglyoxal during aerobic glycolysis while downregulating the detoxification system. We use targeted mutations in mice to modulate methylglyoxal generation and show that reducing methylglyoxal production by the host promotes survival of Listeria monocytogenes and Mycobacterium tuberculosis , whereas increasing methylglyoxal levels improves control of bacterial infection. Furthermore, we show that bacteria that are unable to detoxify methylglyoxal are avirulent and experience up to 1000-fold greater genomic mutation frequency during infection. Taken together, these results suggest that methylglyoxal is an antimicrobial innate immune effector that defends the host against bacterial pathogens.
    DOI:  https://doi.org/10.1101/2024.11.03.621721
  7. J Infect Dis. 2024 Nov 21. pii: jiae583. [Epub ahead of print]
    Genetically diverse Mycobacterium tuberculosis isolates manipulate inflammasome activation and IL-1β secretion independently of macrophage metabolic rewiring.
    Ana Isabel Fernandes, Alexandre Jorge Pinto, Diogo Silvério, Ulrike Zedler, Carolina Ferreira, Iola F Duarte, Ricardo Silvestre, Anca Dorhoi, Margarida Saraiva.
      The diversity of Mycobacterium tuberculosis (Mtb) impacts the outcome of tuberculosis. We previously showed that Mtb isolates obtained from patients with severe disease induced low inflammasome activation and IL-1β production by infected macrophages. Here we questioned whether this differential modulation of macrophages by Mtb isolates depended on distinct metabolic reprogramming. We found that the macrophage metabolic landscape was similar regardless of the infecting Mtb isolate. Paralleling single-TLR activated macrophages, glycolysis inhibition during infection impaired IL-1β secretion. However, departing from TLR based models, in infected macrophages, IL-1β secretion was independent of mitochondrial metabolic changes and HIF-1α. Additionally, we found an unappreciated impact of a host metabolic inhibitor on the pathogen, and show that inflammasome activation and IL-1β production by macrophages require metabolically active bacteria. Our study highlights the potential confounding effect of host metabolic inhibitors on the pathogen and uncouples Mtb-inflammasome modulation from the host metabolic reprogramming.
    Keywords:   Mycobacterium tuberculosis ; immunometabolism; inflammasome; macrophage
    DOI:  https://doi.org/10.1093/infdis/jiae583
  8. J Autoimmun. 2024 Nov 14. pii: S0896-8411(24)00169-0. [Epub ahead of print]149 103335
    Trained innate immunity in response to nuclear antigens in systemic lupus erythematosus.
    Cansu Yanginlar, Nils Rother, Tomas G J M Post, Maaike Jacobs, Inge Jonkman, Montsy Brouns, Sybren Rinzema, Joost H A Martens, Michiel Vermeulen, Leo A B Joosten, Mihai G Netea, Luuk B Hilbrands, Zaheeb A Choudhry, Johan van der Vlag, Raphaël Duivenvoorden.
      Systemic lupus erythematosus (SLE) is an autoimmune disease directed against nuclear antigens, including those derived from apoptotic microparticles (MPs) and neutrophil extracellular traps (NETs). Here we investigated whether nuclear autoantigens can induce trained immunity in SLE patients. Trained immunity is a de facto innate immune memory elicited by an initial stimulus that induces a more vigorous long-term inflammatory response to subsequent stimuli. Isolated monocytes were stimulated with SLE-typical nuclear antigens, neutrophil extracellular traps (NETs), and apoptotic microparticles (MPs) or plasma from SLE patients. After five days of rest, cells were restimulated with Toll-like receptor (TLR) agonists, and cytokine production was measured using ELISA. Functional, transcriptomic and epigenetic changes in monocytes from SLE patients were evaluated by ex vivo stimulations, flow cytometric analysis, RNA sequencing, and chromatin immunoprecipitation (ChIP) sequencing for histone 3 lysine 4 trimethylation. We found that in vitro, both MPs and NETs, as well as plasma from SLE patients, can induce trained immunity. Furthermore, circulating monocytes from SLE patients produce increased levels of pro-inflammatory cytokines after stimulation with TLR ligands, indicating trained immunity. This is accompanied by deregulation in histone 3 lysine 4 trimethylation and increased expression of metabolism and inflammation-related genes. Our findings demonstrate that trained immunity can develop against nuclear antigens and that trained immunity is involved in the immunological dysregulation in SLE patients.
    Keywords:  Innate immune cells; Monocytes; Nuclear antigens; Systemic lupus erythematosus; Trained immunity
    DOI:  https://doi.org/10.1016/j.jaut.2024.103335
  9. bioRxiv. 2024 Nov 02. pii: 2024.11.01.621145. [Epub ahead of print]
    Collagen binding adhesin restricts Staphylococcus aureus skin infection.
    Mohini Bhattacharya, Brady L Spencer, Jakub M Kwiecinski, Magdalena Podkowik, Gregory Putzel, Alejandro Pironti, Bo Shopsin, Kelly S Doran, Alexander R Horswill.
      Staphylococcus aureus causes approximately 80% of skin and soft tissue infections (SSTIs). Collagen is the most abundant human extracellular matrix protein with critical roles in wound healing, and S. aureus encodes a collagen binding adhesin (Cna). The role of this protein during skin infections is unknown. Here we report that inability to bind collagen results in worsened pathology of intradermal δcna S. aureus infection. WT/Cna+ S. aureus showed reduced infection severity, aggregate formation, and significantly improved clearance of bacteria. Cna binds to the collagen-like domain of serum C1q protein to reduce its opsonophagocytic functions. We demonstrate that infection of C1qKO mice with WT bacteria show results similar to the δcna group. Conversely, inability to bind collagen resulted in an amplified inflammatory response caused in part by macrophage and neutrophil small molecule mediators released at the infection site (MMP-9, MMP-12, LTB4), resulting in increased immune cell infiltration and death.
    DOI:  https://doi.org/10.1101/2024.11.01.621145
  10. Glycobiology. 2024 Nov 21. pii: cwae093. [Epub ahead of print]
    Galectin-3 disrupts tight junctions of airway epithelial cell monolayers by inducing expression and release of matrix metalloproteinases upon influenza a infection.
    Muddassar Iqbal, Chiguang Feng, Guanghui Zong, Lai-Xi Wang, Gerardo R Vasta.
      Galectins are β-galactosyl-binding lectins with key roles in early development, immune regulation, and infectious disease. Influenza A virus (IAV) infects the airway epithelia, and in severe cases may lead to bacterial superinfections and hypercytokinemia, and eventually, to acute respiratory distress syndrome (ARDS) through the breakdown of airway barriers. The detailed mechanisms involved, however, remain poorly understood. Our prior in vivo studies in a murine model system revealed that upon experimental IAV and pneumococcal primary and secondary challenges, respectively, galectin-1 and galectin-3 (Gal-3) are released into the airway and bind to the epithelium that has been desialylated by the viral neuraminidase, contributing to secondary bacterial infection and hypercytokinemia leading to the clinical decline and death of the animals. Here we report the results of in vitro studies that reveal the role of the extracellular Gal-3 in additional detrimental effects on the host by disrupting the integrity of the airway epithelial barrier. IAV infection of the human airway epithelia cell line A549 increased release of Gal-3 and its binding to the A549 desialylated cell surface, notably to the transmembrane signaling receptors CD147 and integrin-β1. Addition of recombinant Gal-3 to A549 monolayers resulted in enhanced expression and release of matrix metalloproteinases, leading to disruption of cell-cell tight junctions, and a significant increase in paracellular permeability. This study reveals a critical mechanism involving Gal-3 that may significantly contribute to the severity of IAV infections by promoting disruption of tight junctions and enhanced permeability of the airway epithelia, potentially leading to lung edema and ARDS.
    Keywords:  Cd147; airway epithelial permeability; galectins; influenza; integrin-β1
    DOI:  https://doi.org/10.1093/glycob/cwae093
  11. Nat Immunol. 2024 Nov 20.
    The diverse roles of neutrophils from protection to pathogenesis.
    Rana Herro, H Leighton Grimes.
      Neutrophil granulocytes are the most abundant leukocytes in the blood and constitute a critical arm of innate immunity. They are generated in the bone marrow, and under homeostatic conditions enter the bloodstream to patrol tissues and scout for potential pathogens that they quickly destroy through phagocytosis, intracellular degradation, release of granules and formation of extracellular traps. Thus, neutrophils are important effector cells involved in antibacterial defense. However, neutrophils can also be pathogenic. Emerging data suggest they have critical functions related to tissue repair and fibrosis. Moreover, similarly to other innate immune cells, neutrophil cell states are affected by their microenvironment. Notably, this includes tumors that co-opt neutrophils. Neutrophils can undergo transcriptional and epigenetic reprogramming, thus causing or modulating inflammation and injury. It is also possible that distinct neutrophil subsets are generated with designated functions in the bone marrow. Understanding neutrophil plasticity and alternative cell states will help resolve their contradictive roles. This Review summarizes the most recent key findings surrounding protective versus pathogenic functions of neutrophils; elaborating on phenotype-specific subsets of neutrophils and their involvement in homeostasis and disease.
    DOI:  https://doi.org/10.1038/s41590-024-02006-5
  12. Am J Respir Cell Mol Biol. 2024 Nov 18.
    Spatiotemporal Clusters of ERK Activity Coordinate Cytokine-induced Inflammatory Responses in Human Airway Epithelial Cells.
    Nicholaus L DeCuzzi, Daniel Oberbauer, Kenneth J Chmiel, Michael Pargett, Justa M Ferguson, Devan Murphy, Marion Hardy, Abhineet Ram, Amir A Zeki, John G Albeck.
      Spatially coordinated ERK signaling events ("SPREADs") transmit radially from a central point to adjacent cells via secreted ligands for EGFR and other receptors. SPREADs maintain homeostasis in non-pulmonary epithelia, but it is unknown whether they play a role in the airway epithelium or are dysregulated in inflammatory disease. To address these questions, we measured SPREAD activity with live-cell ERK biosensors in human bronchial epithelial cell lines (HBE1 and 16HBE) and primary human bronchial epithelial (pHBE) cells, in both submerged and biphasic Air-Liquid Interface (ALI) culture conditions (i.e., differentiated cells). Airway epithelial cells were exposed to pro-inflammatory cytokines relevant to asthma and chronic obstructive pulmonary disease (COPD). Type 1 pro-inflammatory cytokines significantly increased the frequency of SPREADs, which coincided with epithelial barrier breakdown in differentiated pHBE cells. Furthermore, SPREADs correlated with IL-6 peptide secretion and the appearance of localized clusters of phospho-STAT3 immunofluorescence. To probe the mechanism of SPREADs, cells were co-treated with pharmacological treatments (gefitinib, tocilizumab, hydrocortisone) or metabolic modulators (insulin, 2-deoxyglucose). Hydrocortisone, inhibitors of receptor signaling, and suppression of metabolic function decreased SPREAD occurrence, implying that pro-inflammatory cytokines and glucose metabolism modulate SPREADs in human airway epithelial cells via secreted EGFR and IL6R ligands. We conclude that spatiotemporal ERK signaling plays a role in barrier homeostasis and dysfunction during inflammation of the airway epithelium. This novel signaling mechanism could be exploited clinically to supplement corticosteroid treatment for asthma and COPD.
    Keywords:  forster resonance energy transfer (FRET); mitogen activated protein kinase (MAPK) , epidermal growth factor receptor (EGFR)
    DOI:  https://doi.org/10.1165/rcmb.2024-0256OC
  13. Future Microbiol. 2024 Nov 21. 1-4
    Next-generation microbiome therapeutics: why it is important to consider the space left in the wake of antibiotic treatment.
    Olivia G King, Victoria Horrocks, Alexander Y G Yip, Julie A K McDonald.
      
    Keywords:  colonization resistance; gut microbiome; metabolite inhibition; microbiome therapeutics; nutrient competition
    DOI:  https://doi.org/10.1080/17460913.2024.2421113
  14. Proc Natl Acad Sci U S A. 2024 Nov 26. 121(48): e2412700121
    TLR priming licenses NAIP inflammasome activation by immunoevasive ligands.
    James P Grayczyk, Luying Liu, Marisa S Egan, Emily Aunins, Meghan A Wynosky-Dolfi, Scott W Canna, Andy J Minn, Sunny Shin, Igor E Brodsky.
      NLR family, apoptosis inhibitory proteins (NAIPs) detect bacterial flagellin and structurally related components of bacterial type III secretion systems (T3SS), and recruit NLR family CARD domain containing protein 4 (NLRC4) and caspase-1 into an inflammasome complex that induces pyroptosis. NAIP/NLRC4 inflammasome assembly is initiated by the binding of a single NAIP to its cognate ligand, but a subset of bacterial flagellins or T3SS structural proteins are thought to evade NAIP/NLRC4 inflammasome sensing by not binding to their cognate NAIPs. Unlike other inflammasome components such as NLRP3, AIM2, or some NAIPs, NLRC4 is constitutively present in resting macrophages and not known to be induced by inflammatory signals. Here, we demonstrate that Toll-like receptor (TLR)-dependent p38 mitogen-activated protein kinase signaling up-regulates NLRC4 transcription and protein expression in murine macrophages, which licenses NAIP detection of evasive ligands. In contrast, TLR priming in human macrophages did not up-regulate NLRC4 expression, and human macrophages remained unable to detect NAIP-evasive ligands even following priming. Critically, ectopic expression of either murine or human NLRC4 was sufficient to induce pyroptosis in response to immunoevasive NAIP ligands, indicating that increased levels of NLRC4 enable the NAIP/NLRC4 inflammasome to detect these normally evasive ligands. Altogether, our data reveal that TLR priming tunes the threshold for the murine NAIP/NLRC4 inflammasome to enable inflammasome responses against immunoevasive or suboptimal NAIP ligands. These findings provide insight into species-specific TLR regulation of NAIP/NLRC4 inflammasome activation.
    Keywords:  Inflammasome; NAIP; NLRC4; Type III secretion; pyroptosis
    DOI:  https://doi.org/10.1073/pnas.2412700121
  15. Int Immunopharmacol. 2024 Nov 19. pii: S1567-5769(24)02155-6. [Epub ahead of print]144 113633
    Liushen Wan alleviates the virulence and inflammation of Staphylococcus aureus via NLRP3 inflammasome and TLR2-NF-κB/p38 MAPK signaling pathways.
    Yudi Song, Qinhai Ma, Jincan Luo, Zifeng Yang, Jiqiang Li, Jin Zhao.
      Infectious diseases have been a major threat to health worldwide, with bacterial infections being particularly prominent. Staphylococcus aureus (S. aureus) infections are associated with the most deaths. Inhibition of virulence factor and excessive inflammation induced by S. aureus has become a potential antibiotic alternative/synergistic therapy without causing greater survival pressure to prevent the emergence of "superbugs" in the future. Liushen Wan (LSW), a traditional Chinese medicine, used for multiple bacterial infectious diseases. In this work, we researched its therapeutic effect and explored the potential mechanism of LSW aiming at S. aureus in vivo and in vitro. Minimal inhibitory concentration (MIC) assay, hemolysis assay, invasion assay, staphyloxanthin assay and evolution of resistance assay were performed to show that LSW alleviated the virulence of S. aureus without suppressing S. aureus activity, and short-term use of LSW did not make bacteria resistant to it. Biofilm inhibition assay demonstrated that LSW inhibited the formation of biofilm and destroyed mature biofilm of S. aureus. In vitro experiments using RT-qPCR, ELISA and western blot analysis indicated LSW inhibited the inflammatory reaction triggered by HK-S. aureus and S. aureus through NLRP3 inflammasome and TLR2-NF-κB/p38 MAPK pathway. Moreover, LSW alleviated lung damage induced by S. aureus. Taken together, LSW is a promising antibacterial, anti-virulence and anti-inflammatory drug, which could provide the pharmacological basis on the traditional application of LSW for diseases associated with S. aureus infection in clinical.
    Keywords:  Inflammation; Liushen Wan; NLRP3; Staphylococcus aureus; TLR2; Virulence factor
    DOI:  https://doi.org/10.1016/j.intimp.2024.113633
  16. NPJ Biofilms Microbiomes. 2024 Nov 20. 10(1): 131
    Staphylococcus epidermidis alters macrophage polarization and phagocytic uptake by extracellular DNA release in vitro.
    Samira Weißelberg, Anna Both, Antonio Virgilio Failla, Jiabin Huang, Stefan Linder, Denise Ohnezeit, Patricia Bartsch, Martin Aepfelbacher, Holger Rohde.
      Biofilm formation shields Staphylococcus epidermidis from host defense mechanisms, contributing to chronic implant infections. Using wild-type S. epidermidis 1457, a PIA-negative mutant (1457-M10), and an eDNA-negative mutant (1457ΔatlE), this study examined the influence of biofilm matrix components on human monocyte-derived macrophage (hMDM) interactions. The wild-type strain was resistant to phagocytosis and induced an anti-inflammatory response in hMDMs, while both mutants were more susceptible to phagocytosis and triggered a pro-inflammatory response. Removing eDNA from the 1457 biofilm matrix increased hMDM uptake and a pro-inflammatory reaction, whereas adding eDNA to the 1457ΔatlE mutant reduced phagocytosis and promoted an anti-inflammatory response. Inhibiting TLR9 enhanced bacterial uptake and induced a pro-inflammatory response in hMDMs exposed to wild-type S. epidermidis. This study highlights the critical role of eDNA in immune evasion and the central role of TLR9 in modulating macrophage responses, advancing the understanding of implant infections.
    DOI:  https://doi.org/10.1038/s41522-024-00604-7
  17. New Microbiol. 2024 Nov;47(3): 195-200
    The Symbiotic Defence: Lung Microbiota and The Local Immune System.
    Ozel Yuruker, İskender Yılmaz, Meryem Güvenir.
      Microbiota defines all microorganisms that are vital for our immunological, hormonal, and metabolic homeostasis by living symbiotically in different parts of our body. On the other hand, the microbiome is a collection of microorganisms that can be detected together. The lungs are constantly exposed to airborne microorganisms found in the upper respiratory tract. Until recently, the lower respiratory tract was considered sterile, as bacteria were rarely isolated from the lungs by conventional culture methods. Most chronic inflammatory lung diseases are caused by dysregulation of the lung microbiota, which has been discussed in many review papers. However, little is known whether microbiota dysymbiosis is a consequence or a cause of these diseases. In this review, we provide an overview of lung microbiota and lung immunity.
    Keywords:  COVID-19; Diseases; Lung; Microbiota
  18. Microb Cell. 2024 ;11 368-377
    Efflux pumps: gatekeepers of antibiotic resistance in Staphylococcus aureus biofilms.
    Shweta Sinha, Shifu Aggarwal, Durg Vijai Singh.
      Staphylococcus aureus, a versatile human pathogen, poses a significant challenge in healthcare settings due to its ability to develop antibiotic resistance and form robust biofilms. Understanding the intricate mechanisms underlying the antibiotic resistance is crucial for effective infection treatment and control. This comprehensive review delves into the multifaceted roles of efflux pumps in S. aureus, with a focus on their contribution to antibiotic resistance and biofilm formation. Efflux pumps, integral components of the bacterial cell membrane, are responsible for expelling a wide range of toxic substances, including antibiotics, from bacterial cells. By actively extruding antibiotics, these pumps reduce intracellular drug concentrations, rendering antibiotics less effective. Moreover, efflux pumps have emerged as significant contributors to both antibiotic resistance and biofilm formation in S. aureus. Biofilms, structured communities of bacterial cells embedded in a protective matrix, enable S. aureus to adhere to surfaces, evade host immune responses, and resist antibiotic therapy. Efflux pumps play a pivotal role in the development and maintenance of S. aureus biofilms. However, the interplay between efflux pumps, antibiotic resistance and biofilm formation remains unexplored in S. aureus. This review aims to elucidate the complex relationship between efflux pumps, antibiotic resistance and biofilm formation in S. aureus with the aim to aid in the development of potential therapeutic targets for combating S. aureus infections, especially those associated with biofilms. The insights provided herein may contribute to the advancement of novel strategies to overcome antibiotic resistance and disrupt biofilm formation in this clinically significant pathogen.
    Keywords:  S aureus; antibiotic resistance; biofilm; efflux pump inhibitors; efflux pumps
    DOI:  https://doi.org/10.15698/mic2024.11.839
  19. Immunol Cell Biol. 2024 Nov 17.
    Prenatal Skin Cell Atlas reveals macrophages' role beyond immunity.
    Céline Pattaroni.
      In this article, we discuss a recently published study by Gopee et al., who have unveiled a surprising role for macrophages in human prenatal skin development, extending far beyond their traditional immune function. By constructing a comprehensive multi-omics single-cell atlas of human prenatal skin, they demonstrate that innate immune cells play a key role in hair follicle formation, scarless wound healing and neurovascular development.
    Keywords:  Human prenatal skin; Prenatal Skin Cell Atlas; human skin development; immunity; innate immune cells; macrophages
    DOI:  https://doi.org/10.1111/imcb.12837
  20. Annu Rev Microbiol. 2024 Nov;78(1): 293-310
    Cell Growth and Division of Staphylococcus aureus.
    Mariana G Pinho, Simon J Foster.
      Bacterial cell growth and division require temporal and spatial coordination of multiple processes to ensure viability and morphogenesis. These mechanisms both determine and are determined by dynamic cellular structures and components, from within the cytoplasm to the cell envelope. The characteristic morphological changes during the cell cycle are largely driven by the architecture and mechanics of the cell wall. A constellation of proteins governs growth and division in Staphylococcus aureus, with counterparts also found in other organisms, alluding to underlying conserved mechanisms. Here, we review the status of knowledge regarding the cell cycle of this important pathogen and describe how this informs our understanding of the action of antibiotics and the specter of antimicrobial resistance.
    Keywords:  antimicrobial resistance; cell cycle; cytokinesis; divisome; penicillin-binding protein; peptidoglycan
    DOI:  https://doi.org/10.1146/annurev-micro-041222-125931
  21. Innate Immun. 2024 Nov 20. 17534259241296630
    Respiratory bioenergetics is enhanced in human, but not bovine macrophages after exposure to M. bovis PPD: Exploratory insights into overall similar Cellular Metabolic Profiles.
    Marie-Christine Bartens, Sam Willcocks, Dirk Werling, Amanda J Gibson.
      The role of macrophage (MØ) cellular metabolism and reprogramming during TB infection is of great interest due to the influence of Mycobacterium spp. on MØ bioenergetics. Recent studies have shown that M. tuberculosis induces a TLR2-dependent shift towards aerobic glycolysis, comparable to the established LPS induced pro-inflammatory M1 MØ polarisation. Distinct differences in the metabolic profile of murine and human MØ indicates species-specific differences in bioenergetics. So far, studies examining the metabolic potential of bovine MØ are lacking, thus the basic bioenergetics of bovine and human MØ were explored in response to a variety of innate immune stimuli. Cellular energy metabolism kinetics were measured concurrently for both species on a Seahorse XFe96 platform to generate bioenergetic profiles for the response to the bona-fide TLR2 and TLR4 ligands, FSL-1 and LPS respectively. Despite previous reports of species-specific differences in TLR signalling and cytokine production between human and bovine MØ, we observed similar respiratory profiles for both species. Basal respiration remained constant between stimulated MØ and controls, whereas addition of TLR ligands induced increased glycolysis, as measured by the surrogate parameter ECAR. In contrast to MØ stimulation with M. tuberculosis PPD, another TLR2 ligand, M. bovis PPD treatment significantly enhanced basal respiration rates and glycolysis only in human MØ. Respiratory profiling further revealed significant elevation of ATP-linked OCR and maximal respiration suggesting a strong OXPHOS activation upon M. bovis PPD stimulation in human MØ. Our results provide an exploratory set of data elucidating the basic respiratory profile of bovine vs. human MØ that will not only lay the foundation for future studies to investigate host-tropism of the M. tuberculosis complex but may explain inflammatory differences observed for other zoonotic diseases.
    Keywords:  BCG; Macrophage; immunometabolism; mycobacteria; tuberculosis
    DOI:  https://doi.org/10.1177/17534259241296630
  22. J Allergy Clin Immunol. 2024 Nov 20. pii: S0091-6749(24)01235-1. [Epub ahead of print]
    A cross-tissue, age-specific flow cytometry reference for immune cells in the airways and blood of children.
    Shivanthan Shanthikumar, Liam Gubbels, Karen Davies, Hannah Walker, Anson Tsz Chun Wong, Jovana Maksimovic, Alicia Oshlack, Richard Saffery, Eric Levi, Sarath C Ranganathan, Melanie R Neeland.
       BACKGROUND: Respiratory diseases are a common cause of morbidity and hospitalisation for children. Despite this, treatment options are limited and are often ineffective. The development of curative or disease-modifying treatments for children relies on a better understanding of underlying immunity in the early airway.
    OBJECTIVE: To establish a flow cytometry dataset for immune cells in the paediatric airway, we analysed 180 samples from 68 children aged between 1-15 years. This included five tissues of the upper (nasal brushings, palatine tonsils, adenotonsil) and lower (bronchial brushings, bronchoalveolar lavage (BAL)) airway, as well as whole blood for paired analysis of local and systemic immune response.
    METHODS: Nasal, bronchial, and alveolar samples were analysed using a 17-plex antibody panel that captures cells of immune and epithelial lineage, while tonsil, adenoid, and blood samples were analysed using a 31-plex antibody panel that extensively phenotypes mononuclear immune cells. All protocols, panels, and data are openly available, to facilitate implementation in paediatric clinical laboratories.
    RESULTS: We provide age-specific airway cell data for infancy (0-2 years), preschool (3-5 years), childhood (6-10 years) and adolescence (11-15 years) for 37 cell populations. We show tissue-specific maturation of the airway immune system across childhood, further highlighting the importance of developing age-specific references of the paediatric airway. Intra-individual, cross-tissue analysis of paired samples revealed marked correlation in immune cell proportions between paired nasal-bronchial samples, paired tonsil-adenoid samples, and paired adenoid-blood samples, which may have implications for clinical testing.
    CONCLUSION: Our study advances knowledge of airway immunity from infancy through to adolescence and provides an openly available control dataset to aid in interpretation of clinical findings in samples obtained from children with respiratory diseases.
    Keywords:  adenoid; airway; alveolar; blood; bronchial; flow cytometry; nasal; pediatrics; reference dataset; tonsil
    DOI:  https://doi.org/10.1016/j.jaci.2024.11.018
  23. Mol Med. 2024 Nov 23. 30(1): 227
    Co-culture of human AT2 cells with fibroblasts reveals a MUC5B phenotype: insights from an organoid model.
    Yiwen Yao, Felix Ritzmann, Sarah Miethe, Kathrin Kattler-Lackes, Betül Colakoglu, Christian Herr, Andreas Kamyschnikow, Michelle Brand, Holger Garn, Daniela Yildiz, Frank Langer, Robert Bals, Christoph Beisswenger.
      Impaired interaction of fibroblasts with pneumocytes contributes to the progression of chronic lung disease such as idiopathic pulmonary fibrosis (IPF). Mucin 5B (MUC5B) is associated with IPF. Here we analyzed the interaction of primary fibroblasts and alveolar type 2 (AT2) pneumocytes in the organoid model. Single-cell analysis, histology, and qRT-PCR revealed that fibroblasts expressing high levels of fibrosis markers regulate STAT3 signaling in AT2 cells, which is accompanied by cystic organoid growth and MUC5B expression. Cystic growth and MUC5B expression were also caused by the cytokine IL-6. The PI3K-Akt signaling pathway was activated in fibroblasts. The drug dasatinib prevented the formation of MUC5B-expressing cystic organoids. MUC5B associated with AT2 cells in samples obtained from IPF patients. Our model shows that fibrotic primary fibroblasts induce impaired differentiation of AT2 cells via STAT3 signaling pathways, as observed in IPF patients. It can be used for mechanistic studies and drug development.
    Keywords:  Fibroblast; IPF; Organoid; Pneumocyte; STAT3
    DOI:  https://doi.org/10.1186/s10020-024-00990-w
  24. bioRxiv. 2024 Nov 05. pii: 2024.11.04.621402. [Epub ahead of print]
    Polymicrobial interactions between Staphylococcus aureus and Pseudomonas aeruginosa promote biofilm formation and persistence in chronic wound infections.
    Klara Keim, Mohini Bhattacharya, Heidi A Crosby, Christian Jenul, Krista Mills, Michael Schurr, Alexander Horswill.
      Chronic, non-healing wounds are a leading cause of prolonged patient morbidity and mortality due to biofilm-associated, polymicrobial infections. Staphylococcus aureus and Pseudomonas aeruginosa are the most frequently co-isolated pathogens from chronic wound infections. Competitive interactions between these pathogens contribute to enhanced virulence, persistence, and antimicrobial tolerance. P. aeruginosa utilizes the extracellular proteases LasB, LasA, and AprA to degrade S. aureus surface structures, disrupt cellular physiology, and induce cell lysis, gaining a competitive advantage during co-infection. S. aureus evades P. aeruginosa by employing aggregation mechanisms to form biofilms. The cell wall protein SasG is implicated in S. aureus biofilm formation by facilitating intercellular aggregation upon cleavage by an extracellular protease. We have previously shown that proteolysis by a host protease can induce aggregation. In this study, we report that P. aeruginosa proteases LasA, LasB, and AprA cleave SasG to induce S. aureus aggregation. We demonstrate that SasG contributes to S. aureus biofilm formation in response to interactions with P. aeruginosa proteases by quantifying aggregation, SasG degradation, and proteolytic kinetics. Additionally, we assess the role of SasG in influencing S. aureus biofilm architecture during co-infection in vivo, chronic wound co-infections. This work provides further knowledge of some of the principal interactions that contribute to S. aureus persistence within chronic wounds co-infected with P. aeruginosa, and their impact on healing and infection outcomes.
    DOI:  https://doi.org/10.1101/2024.11.04.621402
  25. Biochim Biophys Acta Mol Cell Res. 2024 Nov 14. pii: S0167-4889(24)00220-9. [Epub ahead of print]1872(1): 119877
    Targeting SphK1/S1PR3 axis ameliorates sepsis-induced multiple organ injury via orchestration of macrophage polarization and glycolysis.
    Dan Wang, Xinwen Bi, Le Zhao, Shijian Xiang, Wenjie Xi, Shushu Yang, Weijie Wu, Tufeng Chen, Lei Zheng, Xinjin Chi, Yang Kang.
      Sepsis is a heterogeneous and imprecise disorder characterized by aberrant response to infection which has been accredited for detrimental impact on immune homeostasis. Recently, macrophage metabolism has been recognized as attractive targets to develop novel immunomodulatory therapy for sepsis research. However, the fine-tuning regulators dictating macrophage functions and the specific mechanisms underlying macrophage metabolic reprogramming remain largely obscure. Sphingosine-1-phosphate (S1P), a metabolic mediator of sphingolipid catabolism, predominantly formed through sphingosine kinase 1 (SphK1) catalyzing, mediates inflammation in sepsis by binding to S1P receptor 3 (S1PR3) expressed in macrophages. Here we demonstrate that SphK1/S1PR3 axis was upregulated in lipopolysaccharide (LPS)-induced macrophages and septic mice lungs, cascading the activation of proglycolytic signaling such as HIF-1α, HK2 and PFKFB3. Targeted inhibition of Sphk1 by PF-543 effectively abrogated upregulated SphK1/S1PR3 axis in vitro and in vivo. In addition, PF-543 significantly suppressed sepsis-related inflammation and multi-organ injury in vivo. Furthermore, PF-543 not only blunted key glycolytic enzymes HIF-1α, HK2, and PFKFB3 in LPS-treated macrophages but also inhibited HK2 and PFKFB3 in septic mice. Silencing or inhibiting SphK1 tempered pro-inflammatory M1 macrophages while boosted anti-inflammatory M2 macrophages. Intriguingly, S1PR3 knockdown proficiently dampened glycolysis-associated markers, retrieved LPS-modulated M1/M2 polarization and attenuated NF-κB p65 activation. In conclusion, our study provides the first evidence that PF-543 orchestrates proportional imbalance of macrophage polarization and the Warburg effect in a SphK1/S1PR3 dependent manner during sepsis, mitigating both hyperinflammation and multi-organ failure, adding a novel puzzle piece to pharmacologically exploitable therapy for sepsis.
    Keywords:  Glycolysis; Macrophage polarization; Multiple organ injury; Sepsis; SphK1/S1PR3 signaling pathway
    DOI:  https://doi.org/10.1016/j.bbamcr.2024.119877
  26. Front Oncol. 2024 ;14 1449696
    Interactions between tumor-associated macrophages and regulated cell death: therapeutic implications in immuno-oncology.
    Yifei Ge, Lixue Jiang, Chengru Yang, Qingfu Dong, Chengwu Tang, Yi Xu, Xiangyu Zhong.
      Tumor-associated macrophages (TAMs) play a pivotal role in sculpting the tumor microenvironment and influencing cancer progression, particularly through their interactions with various forms of regulated cell death (RCD), including apoptosis, pyroptosis, ferroptosis, and necroptosis. This review examines the interplay between TAMs and these RCD pathways, exploring the mechanisms through which they interact to promote tumor growth and advancement. We examine the underlying mechanisms of these intricate interactions, emphasizing their importance in cancer progression and treatment. Moreover, we present potential therapeutic strategies for targeting TAMs and manipulating RCD to enhance anti-tumor responses. These strategies encompass reprogramming TAMs, inhibiting their recruitment, and selectively eliminating them to enhance anti-tumor functions, alongside modulating RCD pathways to amplify immune responses. These insights offer a novel perspective on tumor biology and provide a foundation for the development of more efficacious cancer therapies.
    Keywords:  apoptosis; cancer therapy; ferroptosis; necroptosis; pyroptosis; regulated cell death; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fonc.2024.1449696
  27. Fish Shellfish Immunol. 2024 Nov 20. pii: S1050-4648(24)00680-6. [Epub ahead of print] 110035
    A preliminary investigation on the protective effects of β-glucan and mannan induced trained immunity in pufferfish Takifugu obscurus.
    Xiaorui Song, Tianying Lei, Nan Cui, Xingkun Jin, Ying Huang, Yan Shi, Zhe Zhao.
      Immune stimuli are able to trigger long-term protective effects through mechanisms of trained immunity, which has attracted increasing attention. Although the existence of trained immunity has evidenced in teleost fish, while there were no such reports in pufferfish (Takifugu obscurus) so far. Therefore, the present study aimed to evaluate the induction of β-glucan and mannan on the trained immunity and their protective efficacy against Vibrio harveyi re-stimulation in pufferfish. β-glucan and mannan induction of trained immunity in head-kidney primary leukocytes is accompanied by a strong increase in immediate ROS burst, cumulative NO production and lactate concentrations after V. harveyi re-stimulation. In addition, β-glucan and mannan-treated pufferfish exhibited reduced bacterial loads in multiple tissues, a rapid and long-term elevated inflammatory response in head kidney during secondary V. harveyi infection. Notably, immune receptors dectin-1 and dectin-2, and cytokines tnfsf14 and il-1β exhibited comparatively upregulation to the β-glucan training, while NK-lysin and faslg showed stronger response to the mannan training post V. harveyi stimulation, implying the different signaling pathway activated post β-glucan and mannan training. Subsequent markers for immune training including abundance of genes encoding glycolytic enzymes (hk1, pfkla, and ldha) and transcription factors (mtor and hif-1α), as well as increased acetylation levels were elevated in the β-glucan and mannan trained pufferfish, depicting heightened glycolysis following β-glucan and mannan training. These results collectively demonstrated that β-glucan and mannan both induced protective responses against V. harveyi infection probably through mediating distinct signaling pathway in pufferfish, and studies are underway to harness its potential applicability for prime and boost vaccination strategies.
    Keywords:  Acetylation level; Mannan; Pufferfish (Takifugu obscurus); Trained immunity; β-glucan
    DOI:  https://doi.org/10.1016/j.fsi.2024.110035
  28. Nature. 2024 Nov 20.
    Your friends shape your microbiome - and so do their friends.
    Saima Sidik.
      
    Keywords:  Computational biology and bioinformatics; Diseases; Microbiology; Microbiome
    DOI:  https://doi.org/10.1038/d41586-024-03804-5
  29. Gene. 2024 Nov 17. pii: S0378-1119(24)00987-9. [Epub ahead of print]936 149106
    Ferroptosis Induces gut microbiota and metabolic dysbiosis in Collagen-Induced arthritis mice via PAD4 enzyme.
    Xiaoying Zhu, Hanya Lu, Wenjing Li, Sijia Niu, Jiawei Xue, Haoyuan Sun, Juan Zhang, Zhiyi Zhang.
      Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation and joint destruction, with emerging evidence implicating gut microbiota dysbiosis in its pathogenesis. The current study explores the role of ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, in modulating gut microbiota and metabolic dysregulation through the enzyme peptidyl arginine deiminase 4 (PAD4) in collagen-induced arthritis (CIA) mouse model. Our findings demonstrate that ferroptosis exacerbates RA-related inflammatory responses and joint damage by upregulating PAD4 expression, which, in turn, influences the gut microbial composition and associated metabolite profiles. Erastin, a known ferroptosis agonist, significantly increased the relative abundance of pro-inflammatory bacteria such as Proteobacteria while reducing beneficial taxa like Firmicutes and Bacteroidetes. This microbial shift was associated with heightened oxidative stress and an imbalance in key metabolites, such as lysophosphatidyl ethanolamine 14:0 (LysoPE 14:0), further exacerbated by ferroptosis. Co-treatment with GSK484, a PAD4 inhibitor, reversed these effects, restoring microbial homeostasis and reducing joint inflammation. This study suggests that ferroptosis-mediated PAD4 activity contributes to RA pathogenesis by disrupting the gut-joint axis, providing novel insights into potential therapeutic targets for RA. Our results highlight the intricate interplay between immune-mediated cell death, gut microbiota, and systemic inflammation, emphasizing the importance of ferroptosis as a therapeutic target in mitigating RA progression.
    Keywords:  Ferroptosis; Gut microbiota; Inflammation; Metabolomics; PAD4; Rheumatoid arthritis
    DOI:  https://doi.org/10.1016/j.gene.2024.149106
  30. Ann Allergy Asthma Immunol. 2024 Nov 14. pii: S1081-1206(24)01657-0. [Epub ahead of print]
    Perturbations in the airway microbiome are associated with type 2 asthma phenotype and severity.
    Wei Zhang, Lifei Li, Yu Zhang, Junjie Dai, Chen Qiu, Rongchang Chen, Fei Shi.
       BACKGROUND: Airway microbiome has been linked to asthma heterogeneity, yet little is known about the associations between airway microbiota and type 2 (T2) asthma phenotype and severity.
    OBJECTIVE: We aimed to determine the relationship of nasopharyngeal (NP) and induced sputum (IS) microbiota to the phenotypic features of T2 asthma.
    METHODS: NP and IS samples from subjects with T2 mild-to-moderate asthma (n=23) and severe asthma (n=21) and healthy controls (n=16) were analyzed. Bacterial microbiota and functional profiles were compared. The correlation between microbial communities and clinical as well as inflammatory features was examined in asthmatics of two statuses.
    RESULTS: Differences in NP and IS microbiota were associated with T2 asthma phenotype. Alterations in NP microbiota were more reflective of T2 inflammation and severity, with additional stratification of a subgroup characterized by significant elevations in T2 inflammatory biomarkers and reductions in bacterial richness and diversity (P < .05). Burkholderia-Caballeronia-Paraburkholderia, Ralstonia and Rhodococcus were identified as hub taxa within NP microbial network in T2 severe asthma, which were prevalent in the entire airway and involved in bacterial functions including inflammatory and steroid responses (P < .05). The composition and diversity of IS microbiota were complex, with Veillonella as the most altered genus, showing an increase with increasing asthma severity.
    CONCLUSION: Our work revealed the significant associations of microbiota perturbations throughout the entire respiratory tract to the extent of T2 inflammation, phenotype and severity in T2 asthma. The specific taxa identified invite further mechanistic investigations to unravel their possibility as biomarkers and therapeutic targets for T2 severe asthma.
    Keywords:  Airway microbiota; Asthma severity; Biomarker; Microbial association networks; T2 inflammation
    DOI:  https://doi.org/10.1016/j.anai.2024.11.005
  31. Trends Immunol. 2024 Nov 19. pii: S1471-4906(24)00253-9. [Epub ahead of print]
    Cytosolic delivery of innate immune agonists.
    Ravi Bharadwaj, Swati Jaiswal, Neal Silverman.
      Solute carrier proteins (SLCs) are pivotal for maintaining cellular homeostasis by transporting small molecules across cellular membranes. Recent discoveries have uncovered their involvement in modulating innate immunity, particularly within the cytosol. We review emerging evidence that links SLC transporters to cytosolic innate immune recognition and highlight their role in regulating inflammation. We explore how SLC transporters influence the activation of endosomal Toll-like receptors, cytosolic NODs, and STING sensors. Understanding the contribution of SLCs to innate immune recognition provides insight into their fundamental biological functions and opens new avenues to develop possible therapeutic interventions for autoimmune and inflammatory diseases. This review aims to discuss current knowledge and identify key gaps in this rapidly evolving field.
    Keywords:  NOD receptors; SLC15; SLC46; STING agonists; cGAMP; muropeptides
    DOI:  https://doi.org/10.1016/j.it.2024.10.007
  32. Mol Cells. 2024 Nov 20. pii: S1016-8478(24)00185-7. [Epub ahead of print] 100160
    Nα-Terminal Acetylation Meets Ferroptosis via N-Degron Pathway.
    Jihye Yang, Cheol-Sang Hwang.
      Cell death can occur through programmed self-destruction, internal sabotage, accidental damage, or immune cell-mediated killing (Green, 2024). Among these, ferroptosis is a regulated, sabotage-type of cell death driven triggered by excessive lipid peroxidation, mostly involving iron, due to imbalances in nutrient, redox, and lipid metabolism (Berndt et al., 2024; Dixon et al., 2012; Green, 2024). Under mild lipid peroxidation, anti-ferroptosis effectors can activate antioxidant defenses, repair cellular damage, or maintain redox balance. However, when lipid peroxidation exceeds a critical threshold, pro-ferroptosis effectors more effectively shift to promoting ferroptosis (Berndt et al., 2024). Furthermore, at critical points, cells are likely to activate both survival and ferroptosis pathways simultaneously, temporarily resisting ferroptosis and sustaining the metastable state between ferroptosis and survival. Supporting this, our recent study on the Na-terminal (Nt-) acetylation-mediated protein degradation system (the Ac/N-degron pathway) suggests a plausible mechanism that concurrently manages these opposing pro-ferroptotic and anti-ferroptotic effectors, potentially influencing cell fate (Figure 1) (Yang et al., 2024).
    Keywords:  Ac/N-degron; N-degron; N-terminal acetylation; cell death; ferroptosis; proteolysis; ubiquitin
    DOI:  https://doi.org/10.1016/j.mocell.2024.100160
  33. Mo Med. 2024 Jul-Aug;121(4):121(4): 310-316
    The Microbiome: From the Beginning to the End.
    Rajeev Aurora, Thomas Sanford.
      The human microbiota, a community of microorganisms in our bodies, is crucial for our health. This paper explores its development from birth through old age, highlighting some of the unique roles at key life stages-infancy, adulthood, and in the elderly years. Understanding the significant health impacts and consequences of changes in the microbiota offers insights for both the public and clinicians.
  34. iScience. 2024 Nov 15. 27(11): 111171
    Human monocyte-derived macrophages shift subcellular metalloprotease activity depending on their activation state.
    Eline Bernaerts, Kourosh Ahmadzadeh, Amber De Visscher, Bert Malengier-Devlies, Daniel Häuβler, Tania Mitera, Erik Martens, Achim Krüger, Lien De Somer, Patrick Matthys, Jennifer Vandooren.
      Proteases are key effectors in macrophage function during the initiation and resolution of inflammation. Recent studies have shown that some proteases, traditionally considered extracellular, also exhibit enzymatic and non-enzymatic functions within the cell. This study explores the differential protease landscapes of macrophages based on their phenotype. Human monocytes were isolated from healthy volunteers and stimulated with M-CSF (resting macrophages), LPS/IFN-γ (inflammatory macrophages), or IL-4 (immunosuppressive macrophages). IL-4-stimulated macrophages secreted higher levels of MMPs and natural protease inhibitors compared to LPS/IFN-γ-stimulated macrophages. Increased extracellular proteolytic activity was detected in LPS/IFN-γ-stimulated macrophages while IL-4 stimulation increased cell-associated proteolytic activity, particularly for MMPs. Subcellular fractionation and confocal microscopy revealed the uptake of extracellular MMP-9 and its relocation to the nucleus in IL-4-stimulated, though not in LPS/IFN-γ-stimulated macrophages. Collectively, macrophages alter the subcellular location and activity of their MMPs based on the stimuli received, suggesting another mechanism for protease regulation in macrophage biology.
    Keywords:  Biological sciences; Immune response; Immunology; Natural sciences
    DOI:  https://doi.org/10.1016/j.isci.2024.111171
  35. mSphere. 2024 Nov 21. e0089324
    Erratum for Hassall et al., "Dissecting Individual Interactions between Pathogenic and Commensal Bacteria within a Multispecies Gut Microbial Community".
    Jack Hassall, Jeffery K J Cheng, Meera Unnikrishnan.
      
    DOI:  https://doi.org/10.1128/msphere.00893-24
  36. MedComm (2020). 2024 Dec;5(12): e70012
    Gut microbiota in health and disease: advances and future prospects.
    Yusheng Zhang, Hong Wang, Yiwei Sang, Mei Liu, Qing Wang, Hongjun Yang, Xianyu Li.
      The gut microbiota plays a critical role in maintaining human health, influencing a wide range of physiological processes, including immune regulation, metabolism, and neurological function. Recent studies have shown that imbalances in gut microbiota composition can contribute to the onset and progression of various diseases, such as metabolic disorders (e.g., obesity and diabetes) and neurodegenerative conditions (e.g., Alzheimer's and Parkinson's). These conditions are often accompanied by chronic inflammation and dysregulated immune responses, which are closely linked to specific forms of cell death, including pyroptosis and ferroptosis. Pathogenic bacteria in the gut can trigger these cell death pathways through toxin release, while probiotics have been found to mitigate these effects by modulating immune responses. Despite these insights, the precise mechanisms through which the gut microbiota influences these diseases remain insufficiently understood. This review consolidates recent findings on the impact of gut microbiota in these immune-mediated and inflammation-associated conditions. It also identifies gaps in current research and explores the potential of advanced technologies, such as organ-on-chip models and the microbiome-gut-organ axis, for deepening our understanding. Emerging tools, including single-bacterium omics and spatial metabolomics, are discussed for their promise in elucidating the microbiota's role in disease development.
    Keywords:  cell death; ferroptosis; gut microbiota; microbiome–gut–organ axis chip; pyroptosis; single‐bacterium omics
    DOI:  https://doi.org/10.1002/mco2.70012
  37. Int Immunopharmacol. 2024 Nov 15. pii: S1567-5769(24)02145-3. [Epub ahead of print]143(Pt 3): 113623
    ASIC1a regulates airway epithelial cell pyroptosis in acute lung injury by NLRP3-Caspase1-GSDMD pathway.
    Yuan-Yuan Tan, Da-Wei Zhang, Chun Yang, Yan Huang, Jia-Ying Kang, Zhong-Hua Xu, Yuan-Yuan Wei, Zhen-Xing Ding, Guang-He Fei.
       BACKGROUND: Acidosis is the most common complication that seriously affects the prognosis of acute respiratory distress syndrome (ARDS). Acid-sensitive ion channel 1a (ASIC1a) is activated in acidic environments to regulate inflammatory process. However, the role of ASIC1a in ARDS is unclear.
    METHODS: In this study, we examined the expression of ASIC1a in airway epithelial cells in an acidic environment. We then investigated whether blocking ASIC1a could inhibit pyroptosis of airway epithelial cells and the molecular mechanism. In the mouse acute lung injury (ALI) model, we observed the changes of lung histopathology, arterial blood gas and pyroptosis related indexes after ASIC1a inhibition. Bronchoalveolar lavage fluid (BALF) from patients with ARDS were collected to explore the expression level of ASIC1a in ARDS patients.
    RESULTS: Inhibiting ASIC1a can reduce the airway epithelial cell pyroptosis induced by an extracellular acidic environment. ASIC1a can bind to PRKACA, and silencing ASIC1a and PRKACA can inhibit the occurrence of pyroptosis in airway epithelial cells. Compared with control group, arterial blood pH and PaO2 in ALI group were significantly reduced. The inflammation in the lungs is more intense, and the mRNA and protein of NLRP3, Caspase1 and GSDMD were increased, while ASIC1a specific blocker psalmotoxin-1 alleviated this phenomenon. The expression of ASIC1a in BALF of ARDS patients was significantly increased, especially in non-survival group.
    CONCLUSION: Acidic micro-environment can induce the increased expression of ASIC1a, and inhibition of ASIC1a can alleviate the inflammation and airway epithelial cell pyroptosis in ARDS. ASIC1a may be a new target for the treatment of ARDS.
    Keywords:  ARDS; ASIC1a; Acidic micro-environment; Lung injury; Pyroptosis
    DOI:  https://doi.org/10.1016/j.intimp.2024.113623
  38. Clin Transl Med. 2024 Nov;14(11): e70093
    Disentangling the molecular mystery of tumour-microbiota interactions: Microbial metabolites.
    Yu-Fei Duan, Jia-Hao Dai, Ying-Qi Lu, Han Qiao, Na Liu.
      The profound impact of the microbiota on the initiation and progression of cancer has been a focus of attention. In recent years, many studies have shown that microbial metabolites serve as key hubs that connect the microbiome and cancer progression, but the underlying molecular mechanisms have not been fully elucidated. Multiple mechanisms that influence tumour development and therapy resistance, including disrupting cellular signalling pathways, triggering oxidative stress, inducing metabolic reprogramming and reshaping tumour immune microenvironment, are reviewed. Focusing on recent advancements in this field, this review also summarises the methodological framework of studies regarding microbial metabolites. In this review, we outline the current state of research on tumour-associated microbial metabolites and describe the challenges in future scientific research and clinical applications. KEY POINTS: Metabolites derived from both gut and intratumoural microbiota play important roles in cancer initiation and progression. The dual roles of microbial metabolites pose an obstacle for clinical translations. Absolute quantification and tracing techniques of microbial metabolites are essential for addressing the gaps in studies on microbial metabolites. Integrating microbial metabolomics with multi-omics transcends current research paradigms.
    Keywords:  cancer; functional mechanisms; microbial metabolites; microbial metabolomics
    DOI:  https://doi.org/10.1002/ctm2.70093
  39. Immunol Rev. 2024 Nov 23.
    Immunoglobulin A Antibodies: From Protection to Harmful Roles.
    Patrick J Gleeson, Niels O S Camara, Pierre Launay, Agnès Lehuen, Renato C Monteiro.
      Immunoglobulin A (IgA) is the most abundantly produced antibody in humans. IgA is a unique class of immunoglobulin due to its multiple molecular forms, and a defining difference between the two subclasses: IgA1 has a long hinge-region that is heavily O-glycosylated, whereas the IgA2 hinge-region is shorter but resistant to bacterial proteases prevalent at mucosal sites. IgA is essential for immune homeostasis and education. Mucosal IgA plays a crucial role in maintaining the integrity of the mucosal barrier by immune exclusion of pathobionts while facilitating colonization with certain commensals; a large part of the gut microbiota is coated with IgA. In the circulation, monomeric IgA that has not been engaged by antigen plays a discrete role in dampening inflammatory responses. Protective and harmful roles of IgA have been studied over several decades, but a new understanding of the complex role of this immunoglobulin in health and disease has been provided by recent studies. Here, we discuss the physiological and pathological roles of IgA with a special focus on the gut, kidneys, and autoimmunity. We also discuss new IgA-based therapeutic approaches.
    Keywords:  immunoglobulin A; inflammation; microbiota; mucosal immunity
    DOI:  https://doi.org/10.1111/imr.13424
  40. Blood. 2024 Nov 22. pii: blood.2024025680. [Epub ahead of print]
    The Contribution of the Monocyte-Macrophage Lineage to Immunotherapy Outcomes.
    Rachael C Adams, Kelli Pa MacDonald, Geoffrey R Hill.
      Macrophages execute core functions in maintaining tissue homeostasis, where their extensive plasticity permits a spectrum of functions from tissue remodelling to immune defence. However, perturbations to tissue-resident macrophages during disease, and the subsequent emergence of monocyte-derived macrophages, can hinder tissue recovery and promote further damage through inflammatory and fibrotic programs. Gaining a fundamental understanding of the critical pathways defining pathogenic macrophage populations enables the development of targeted therapeutic approaches to improve disease outcomes. In the setting of chronic graft-versus-host disease (cGVHD), which remains the major complication of allogeneic haematopoietic stem cell transplantation, colony-stimulating factor 1 (CSF1)-dependent donor-derived macrophages have been identified as key pathogenic mediators of fibrotic skin and lung disease. Antibody blockade of the CSF1R to induce macrophage depletion showed remarkable capacity to prevent fibrosis in pre-clinical models and has subsequently demonstrated impressive efficacy for improving fibrotic cGVHD in ongoing clinical trials. Similarly, macrophage depletion approaches are currently under investigation for their potential to augment responses to immune checkpoint inhibition. Moreover, both monocyte and tissue-resident macrophage populations have recently been implicated as mediators of the numerous toxicities associated with CAR T-cell therapy, further highlighting potential avenues of macrophage-based interventions to improve clinical outcomes. Herein, we examine the current literature on basic macrophage biology and contextualise this in the setting of cellular and immunotherapy. Additionally, we highlight mechanisms by which macrophages can be targeted, largely by interfering with the CSF1/CSF1R signalling axis, for therapeutic benefit in the context of both cellular and immunotherapy.
    DOI:  https://doi.org/10.1182/blood.2024025680
  41. MedComm (2020). 2024 Dec;5(12): e70010
    Ferroptosis: mechanisms and therapeutic targets.
    Qian Zhou, Yu Meng, Jiayuan Le, Yuming Sun, Yating Dian, Lei Yao, Yixiao Xiong, Furong Zeng, Xiang Chen, Guangtong Deng.
      Ferroptosis is a nonapoptotic form of cell death characterized by iron-dependent lipid peroxidation in membrane phospholipids. Since its identification in 2012, extensive research has unveiled its involvement in the pathophysiology of numerous diseases, including cancers, neurodegenerative disorders, organ injuries, infectious diseases, autoimmune conditions, metabolic disorders, and skin diseases. Oxidizable lipids, overload iron, and compromised antioxidant systems are known as critical prerequisites for driving overwhelming lipid peroxidation, ultimately leading to plasma membrane rupture and ferroptotic cell death. However, the precise regulatory networks governing ferroptosis and ferroptosis-targeted therapy in these diseases remain largely undefined, hindering the development of pharmacological agonists and antagonists. In this review, we first elucidate core mechanisms of ferroptosis and summarize its epigenetic modifications (e.g., histone modifications, DNA methylation, noncoding RNAs, and N6-methyladenosine modification) and nonepigenetic modifications (e.g., genetic mutations, transcriptional regulation, and posttranslational modifications). We then discuss the association between ferroptosis and disease pathogenesis and explore therapeutic approaches for targeting ferroptosis. We also introduce potential clinical monitoring strategies for ferroptosis. Finally, we put forward several unresolved issues in which progress is needed to better understand ferroptosis. We hope this review will offer promise for the clinical application of ferroptosis-targeted therapies in the context of human health and disease.
    Keywords:  epigenetics; ferroptosis; human disease; lipid peroxidation
    DOI:  https://doi.org/10.1002/mco2.70010
  42. Cell Mol Immunol. 2024 Nov 22.
    Gasdermin D unlocks metabolic pathways to enhance tissue regeneration.
    Quazi T H Shubhra.
      
    DOI:  https://doi.org/10.1038/s41423-024-01239-6
  43. PLoS Biol. 2024 Nov 18. 22(11): e3002907
    Niche-specific metabolic phenotypes can be used to identify antimicrobial targets in pathogens.
    Emma M Glass, Lillian R Dillard, Glynis L Kolling, Andrew S Warren, Jason A Papin.
      Bacterial pathogens pose a major risk to human health, leading to tens of millions of deaths annually and significant global economic losses. While bacterial infections are typically treated with antibiotic regimens, there has been a rapid emergence of antimicrobial resistant (AMR) bacterial strains due to antibiotic overuse. Because of this, treatment of infections with traditional antimicrobials has become increasingly difficult, necessitating the development of innovative approaches for deeply understanding pathogen function. To combat issues presented by broad- spectrum antibiotics, the idea of narrow-spectrum antibiotics has been previously proposed and explored. Rather than interrupting universal bacterial cellular processes, narrow-spectrum antibiotics work by targeting specific functions or essential genes in certain species or subgroups of bacteria. Here, we generate a collection of genome-scale metabolic network reconstructions (GENREs) of pathogens through an automated computational pipeline. We used these GENREs to identify subgroups of pathogens that share unique metabolic phenotypes and determined that pathogen physiological niche plays a role in the development of unique metabolic function. For example, we identified several unique metabolic phenotypes specific to stomach pathogens. We identified essential genes unique to stomach pathogens in silico and a corresponding inhibitory compound for a uniquely essential gene. We then validated our in silico predictions with an in vitro microbial growth assay. We demonstrated that the inhibition of a uniquely essential gene, thyX, inhibited growth of stomach-specific pathogens exclusively, indicating possible physiological location-specific targeting. This pioneering computational approach could lead to the identification of unique metabolic signatures to inform future targeted, physiological location-specific, antimicrobial therapies, reducing the need for broad-spectrum antibiotics.
    DOI:  https://doi.org/10.1371/journal.pbio.3002907
  44. Immunity. 2024 Nov 14. pii: S1074-7613(24)00490-4. [Epub ahead of print]
    A pan-family screen of nuclear receptors in immunocytes reveals ligand-dependent inflammasome control.
    Yutao Wang, Yanbo Zhang, Kyungsub Kim, Jichang Han, Daniel Okin, Zhaozhao Jiang, Liang Yang, Arum Subramaniam, Terry K Means, Frank O Nestlé, Katherine A Fitzgerald, Gwendalyn J Randolph, Cammie F Lesser, Jonathan C Kagan, Diane Mathis, Christophe Benoist.
      Ligand-dependent transcription factors of the nuclear receptor (NR) family regulate diverse aspects of metazoan biology, enabling communications between distant organs via small lipophilic molecules. Here, we examined the impact of each of 35 NRs on differentiation and homeostatic maintenance of all major immunological cell types in vivo through a "Rainbow-CRISPR" screen. Receptors for retinoic acid exerted the most frequent cell-specific roles. NR requirements varied for resident macrophages of different tissues. Deletion of either Rxra or Rarg reduced frequencies of GATA6+ large peritoneal macrophages (LPMs). Retinoid X receptor alpha (RXRα) functioned conventionally by orchestrating LPM differentiation through chromatin and transcriptional regulation, whereas retinoic acid receptor gamma (RARγ) controlled LPM survival by regulating pyroptosis via association with the inflammasome adaptor ASC. RARγ antagonists activated caspases, and RARγ agonists inhibited cell death induced by several inflammasome activators. Our findings provide a broad view of NR function in the immune system and reveal a noncanonical role for a retinoid receptor in modulating inflammasome pathways.
    DOI:  https://doi.org/10.1016/j.immuni.2024.10.010
  45. Science. 2024 Nov 22. 386(6724): 850-851
    Macrophage modulation of tumor immunity.
    Peter Savage.
      Macrophages deliver polarizing messages to promote immune suppression in tumors.
    DOI:  https://doi.org/10.1126/science.adt5661
  46. Carbohydr Res. 2024 Nov 10. pii: S0008-6215(24)00288-X. [Epub ahead of print]546 109309
    Relationships between bacteria and the mucus layer.
    Inka Brockhausen, Dylan Falconer, Sara Sara.
      The mucus layer on epithelial cells is an essential barrier, as well as a nutrient-rich niche for bacteria, forming a dynamic, functional and symbiotic ecosystem and first line of defense against invading pathogens. Particularly bacteria in biofilms are very difficult to eradicate. The extensively O-glycosylated mucins are the main glycoproteins in mucus that interact with microbes. For example, mucins act as adhesion receptors and nutritional substrates for gut bacteria. Mucins also play important roles in immune responses, and they control the composition of the microbiome, primarily due to the abundance of complex O-glycans. In inflammation or infection, the structures of mucin O-glycans can change and thus affect mucin function, impact biofilm formation and the induction of virulence pathways in bacteria. In turn, bacteria can support host cell growth, mucin production and can stimulate changes in the host immune system and responses leading to healthy tissue function. The external polysaccharides of bacteria are critical for controlling adhesion and biofilm formation. It is therefore important to understand the relationships between the mucus layer and microbes, the mechanisms and regulation of the biosynthesis of mucins, of bacterial surface polysaccharides, and adhesins. This knowledge can provide biomarkers, vaccines and help to develop new approaches for improved therapies, including antibiotic treatments.
    Keywords:  Adhesion; Bacteria; Biofilm; Epithelium; Mucins; Mucus; O-glycans
    DOI:  https://doi.org/10.1016/j.carres.2024.109309
  47. Nat Commun. 2024 Nov 23. 15(1): 10157
    PDCD6 regulates lactate metabolism to modulate LC3-associated phagocytosis and antibacterial defense.
    Lulu Sun, Sijin Wu, Hui Wang, Tianyu Zhang, Mengyu Zhang, Xuepeng Bai, Xiumei Zhang, Bingqing Li, Cai Zhang, Yan Li, Jun Zhou, Tianliang Li.
      LC3-associated phagocytosis (LAP) is critical in host defense against invading pathogens, but the molecular mechanism for LAP activation is still unclear. Here, we find programmed cell death 6 (PDCD6) as a negative regulator of LAP. PDCD6 deficiency in mice and macrophages induces enhanced bactericidal activity and LAP formation. In parallel, lactate dehydrogenase A (LDHA) activity and lactate production is induced in macrophages challenged with bacteria, Zymosan or Pam3CSK4, while genetic ablation or pharmacological inhibition of LDHA reduces lactate levels and impairs bactericidal activity in vivo and in vitro. Mechanistically, PDCD6 interacts with LDHA to downregulate lactate metabolism, leading to reduced RUBCN lactylation at lysine33 (K33). By contrast, PDCD6-deficiency increases RUBCN lactylation, thereby promotes RUBCN interaction with VPS34, LAP formation, and protective responses. Our results thus suggest a PDCD6-LDHA-lactate-RUBCN axis of innate immunity regulation that may both contribute to protection from infectious diseases and serve as targets for therapeutic development.
    DOI:  https://doi.org/10.1038/s41467-024-54377-w
  48. Nature. 2024 Nov 20.
    Spatially restricted immune and microbiota-driven adaptation of the gut.
    Toufic Mayassi, Chenhao Li, Åsa Segerstolpe, Eric M Brown, Rebecca Weisberg, Toru Nakata, Hiroshi Yano, Paula Herbst, David Artis, Daniel B Graham, Ramnik J Xavier.
      The intestine is characterized by an environment in which host requirements for nutrient and water absorption are consequently paired with the requirements to establish tolerance to the outside environment. To better understand how the intestine functions in health and disease, large efforts have been made to characterize the identity and composition of cells from different intestinal regions1-8. However, the robustness, nature of adaptability and extent of resilience of the transcriptional landscape and cellular underpinning of the intestine in space are still poorly understood. Here we generated an integrated resource of the spatial and cellular landscape of the murine intestine in the steady and perturbed states. Leveraging these data, we demonstrated that the spatial landscape of the intestine was robust to the influence of the microbiota and was adaptable in a spatially restricted manner. Deploying a model of spatiotemporal acute inflammation, we demonstrated that both robust and adaptable features of the landscape were resilient. Moreover, highlighting the physiological relevance and value of our dataset, we identified a region of the middle colon characterized by an immune-driven multicellular spatial adaptation of structural cells to the microbiota. Our results demonstrate that intestinal regionalization is characterized by robust and resilient structural cell states and that the intestine can adapt to environmental stress in a spatially controlled manner through the crosstalk between immunity and structural cell homeostasis.
    DOI:  https://doi.org/10.1038/s41586-024-08216-z
  49. PLoS Pathog. 2024 Nov 18. 20(11): e1012696
    Mucosal immunization with the lung Lactobacillus-derived amphiphilic exopolysaccharide adjuvanted recombinant vaccine improved protection against P. aeruginosa infection.
    Haochi Zhang, Shouxin Sheng, Chunhe Li, Xuemei Bao, Lixia Zhao, Jian Chen, Pingyuan Guan, Xiaoyan Li, Na Pan, Yanchen Liang, Xueqi Wang, Jingmin Sun, Xiao Wang.
      Respiratory infections caused by Pseudomonas aeruginosa are a major health problem globally. Current treatment for P. aeruginosa infections relies solely on antibiotics, but the rise of antibiotic-resistant strains necessitates an urgent need for a protective vaccine. Traditional parenteral vaccines, despite employing potent adjuvants aimed at serotype-dependent immunity, often fail to elicit the desired mucosal immune response. Thus, developing vaccines that target both localized mucosal and systemic immune responses represents a promising direction for future research on P. aeruginosa vaccination. In this study, we explored EPS301, the exopolysaccharide derived from the lung microbiota strain Lactobacillus plantarum WXD301, which exhibits excellent self-assembly properties, enabling the formation of homogeneous nanoparticles when encapsulating recombinant PcrV of P. aeruginosa, designated as EPS301@rPcrV. Notably, the EPS301 vector effectively enhanced antigen adhesion to the nasal and pulmonary mucosal tissues and prolonged antigen retention. Moreover, EPS301@rPcrV provided effective and sustained protection against P. aeruginosa pneumonia, surpassing the durability achieved with the "gold standard" cholera toxin adjuvant. The EPS301-adjuvanted vaccine formulation elicited robust mucosal IgA and Th17/γδ17 T cell responses, which exceeded those induced by the CTB-adjuvanted vaccination and were sustained for over 112 days. Additionally, Th 17 and γδ 17 resident memory T cells induced by EPS301@rPcrV were crucial for protection against P. aeruginosa challenge. Intriguingly, IL-17A knockout mice exhibited lower survival rates, impaired bacterial clearance ability, and exacerbated lung tissue damage upon EPS301 adjuvanted vaccination against P. aeruginosa-induced pneumonia, indicating an IL-17A-dependent protective mechanism. In conclusion, our findings provided direct evidence that EPS301@rPcrV mucosal vaccine is a promising candidate for future clinical application against P. aeruginosa-induced pulmonary infection.
    DOI:  https://doi.org/10.1371/journal.ppat.1012696
  50. Allergy. 2024 Nov 23.
    Downregulation of Tight Junction Protein MAGI1 by Interferon-γ Contributes to Barrier Dysfunction in Chronic Rhinosinusitis With Nasal Polyps.
    Jing Song, Chaoran Zhao, Enhao Wang, Jing Yuan, Chengshuo Wang, Ming Wang, Luo Zhang.
      
    DOI:  https://doi.org/10.1111/all.16405
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