bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2025–01–19
fifty-one papers selected by
Chun-Chi Chang, Universitäts Spital Zürich
  1. Friends to remember: innate immune memory regulation by the microbiota.
  2. Early and delayed STAT1-dependent responses drive local trained immunity of macrophages in the spleen.
  3. Role of Trained Immunity in Heath and Disease.
  4. Phagocytosis by macrophages decreases the radiance of bioluminescent Staphylococcus aureus.
  5. The mutational landscape of Staphylococcus aureus during colonisation.
  6. Nasal microbiota transplantation: a gateway to novel treatments.
  7. Plasticity of cell death pathways ensures GSDMD activation during Yersinia pseudotuberculosis infection.
  8. Ticam2 ablation facilitates monocyte exhaustion recovery after sepsis.
  9. DAMPs, PAMPs, NLRs, RIGs, CLRs and TLRs - Understanding the Alphabet Soup in the Context of Bone Biology.
  10. A stretchable human lung-on-chip model of alveolar inflammation for evaluating anti-inflammatory drug response.
  11. Gasdermin pores on extracellular vesicles spread cell death.
  12. Nasal microbiota predictors for methicillin resistant Staphylococcus colonization in critically ill children.
  13. Tumor-induced metabolic immunosuppression: Mechanisms and therapeutic targets.
  14. IL-8 promotes pyroptosis through ERK pathway and mediates glucocorticoid resistance in chronic rhinosinusitis with nasal polyps.
  15. TRIF-TAK1 signaling suppresses caspase-8/3-mediated GSDMD/E activation and pyroptosis in influenza A virus-infected airway epithelial cells.
  16. Macrophage Polarization: Learning to Manage It 3.0.
  17. Menin orchestrates macrophage reprogramming to maintain the pulmonary immune homeostasis.
  18. A Multicellular In Vitro Model of the Human Intestine with Immunocompetent Features Highlights Host-Pathogen Interactions During Early Salmonella Typhimurium Infection.
  19. These are the 20 most-studied bacteria - the majority have been ignored.
  20. Alveolar Macrophages in Viral Respiratory Infections: Sentinels and Saboteurs of Lung Defense.
  21. Inhibition of Mitochondrial Succinate Dehydrogenase with Dimethyl Malonate Promotes M2 Macrophage Polarization by Enhancing STAT6 Activation.
  22. Spatio-Temporal Change of Skin and Oral Microbiota: A Longitudinal Study of Microbial Diversity and Stability.
  23. Regulatory Roles of Noncanonical Inflammasomes in Inflammatory Lung Diseases.
  24. Pathogenic Colonization: Defining the Role of Staphylococcus aureus in Atopic Dermatitis.
  25. Single-cell analysis reveals Mycobacterium tuberculosis ESX-1-mediated accumulation of permissive macrophages in infected mouse lungs.
  26. Ferroptosis: A Targetable Vulnerability for Melanoma Treatment.
  27. Bifidobacterium longum RAPO Attenuates Dermal and Pulmonary Fibrosis in a Mouse Model of Systemic Sclerosis through Macrophage Modulation and Growth of Short-Chain Fatty Acid Producers.
  28. Recent developments in myeloid immune modulation in cancer therapy.
  29. Emerging Concepts in Periprosthetic Joint Infection Research: The Human Microbiome.
  30. Piezo1-Induced Nasal Epithelial Barrier Dysfunction in Allergic Rhinitis.
  31. A BCG kill switch strain protects against Mycobacterium tuberculosis in mice and non-human primates with improved safety and immunogenicity.
  32. Emerging models to study competitive interactions within bacterial communities.
  33. Comparison of cell-scaffold interactions in a biological and a synthetic wound matrix.
  34. Roles of oolong tea extracts in the protection against Staphylococcus aureus infection in Caenorhabditis elegans.
  35. Clinical implications of maternal multikingdom transmissions and early-life microbiota.
  36. Staphylococcus aureus: Dynamics of pathogenicity and antimicrobial-resistance in hospital and community environments - Comprehensive overview.
  37. Transient comparison of techniques to counter multi-drug resistant bacteria: prime modules in curation of bacterial infections.
  38. Protocol for the Generation and 3D Culture of Fluorescently Labeled Multicellular Spheroids.
  39. Tracheal tuft cells release ATP and link innate to adaptive immunity in pneumonia.
  40. Langerhans Cells Directly Interact with Resident T Cells in the Human Epidermis.
  41. Deficient neutrophil responses early in influenza infection promote viral replication and pulmonary inflammation.
  42. The endothelium at the interface between tissues and Staphylococcus aureus in the bloodstream.
  43. SMEPPI: An indenone derivative that selectively inhibits M1 macrophage activation and enhances phagocytic activity.
  44. Tissue-resident immune cells: from defining characteristics to roles in diseases.
  45. A novel human fetal lung-derived alveolar organoid model reveals mechanisms of surfactant protein C maturation relevant to interstitial lung disease.
  46. Multi-omic analysis of chronic myelomonocytic leukemia monocytes reveals metabolic and immune dysregulation leading to altered macrophage polarization.
  47. Nuclear adenine activates hnRNPA2B1 to enhance antibacterial innate immunity.
  48. H3K14la drives endothelial dysfunction in sepsis-induced ARDS by promoting SLC40A1/transferrin-mediated ferroptosis.
  49. Bacteria in hypertrophic scars promote scar formation through HSBP1-mediated autophagy.
  50. Proximity Labeling and Genetic Screening Reveal that DSG2 is a Counter Receptor of Siglec-9 and Suppresses Macrophage Phagocytosis.
  51. Mitochondria and NLRP3: To die or inflame.
  1. Trends Microbiol. 2025 Jan 09. pii: S0966-842X(24)00318-4. [Epub ahead of print]
    Friends to remember: innate immune memory regulation by the microbiota.
    Aize Pellon, Ainhoa Palacios, Leticia Abecia, Héctor Rodríguez, Juan Anguita.
      Innate immune memory (IIM) is the process by which, upon a primary challenge, innate immune cells alter their epigenetic, transcriptional, and immunometabolic profiles, resulting in modified secondary responses. Unlike infections or other immune-system-related diseases, the role of IIM in nonpathogenic contexts is less understood. An increasing body of research has shown that normal microbiota members or their metabolic byproducts induce alternative memory phenotypes, suggesting that memory cells contribute to homeostasis in mucosal areas. In this review, we discuss the newest insights in the emerging field of IIM to the microbiota and the potential of manipulating these long-term responses to promote better mucosal health.
    Keywords:  immunometabolism; innate immune memory; microbiota; tolerance; trained immunity
    DOI:  https://doi.org/10.1016/j.tim.2024.12.002
  2. Elife. 2025 Jan 16. pii: RP100922. [Epub ahead of print]13
    Early and delayed STAT1-dependent responses drive local trained immunity of macrophages in the spleen.
    Aryeh Solomon, Noa Bossel Ben-Moshe, Dotan Hoffman, Sébastien Trzebanski, Dror Yehezkel, Leia Vainman, Mihai G Netea, Roi Avraham.
      Trained immunity (TI) is the process wherein innate immune cells gain functional memory upon exposure to specific ligands or pathogens, leading to augmented inflammatory responses and pathogen clearance upon secondary exposure. While the differentiation of hematopoietic stem cells (HSCs) and reprogramming of bone marrow (BM) progenitors are well-established mechanisms underpinning durable TI protection, remodeling of the cellular architecture within the tissue during TI remains underexplored. Here, we study the effects of peritoneal Bacillus Calmette-Guérin (BCG) administration to find TI-mediated protection in the spleen against a subsequent heterologous infection by the Gram-negative pathogen Salmonella Typhimurium (S.Tm). Utilizing single cell RNA-sequencing and flow cytometry, we discerned STAT1-regulated genes in TI-associated resident and recruited splenic myeloid populations. The temporal dynamics of TI were further elucidated, revealing both early and delayed myeloid subsets with time-dependent, cell-type-specific STAT1 signatures. Using lineage tracing, we find that tissue-resident red pulp macrophages (RPM), initially depleted by BCG exposure, are restored from both tissue-trained, self-renewing macrophages and from bone marrow-derived progenitors, fostering long lasting local defense. Early inhibition of STAT1 activation, using specific JAK-STAT inhibitors, reduces both RPM loss and recruitment of trained monocytes. Our study suggests a temporal window soon after BCG vaccination, in which STAT1-dependent activation of long-lived resident cells in the tissue mediates localized protection.
    Keywords:  BCG; Salmonella; immunology; inflammation; macrophages; mouse
    DOI:  https://doi.org/10.7554/eLife.100922
  3. Curr Cardiol Rep. 2025 Jan 13. 27(1): 18
    Role of Trained Immunity in Heath and Disease.
    Shibali Das, Kory J Lavine.
       PURPOSE OF REVIEW: This review aims to explore the role of immune memory and trained immunity, focusing on how innate immune cells like monocytes, macrophages, and natural killer cells undergo long-term epigenetic and metabolic rewiring. Specifically, it examines the mechanisms by which trained immunity, often triggered by infection or vaccination, could impact cardiac processes and contribute to both protective and pathological responses within the cardiovascular system.
    RECENT FINDINGS: Recent research demonstrates that vaccination and infection not only activate immune responses in circulating monocytes and tissue macrophages but also affect immune progenitor cells within the bone marrow environment, conferring lasting protection against heterologous infections. These protective effects are attributed to epigenetic and metabolic reprogramming, which enable a heightened immune response upon subsequent encounters with pathogens. However, while trained immunity is beneficial in combating infections, it has been linked to exacerbated inflammation, which may increase susceptibility to cardiovascular diseases, including atherosclerosis and heart failure. Our review highlights the dual nature of trained immunity: while it offers protective advantages against infections, it also poses potential risks for cardiovascular health by promoting chronic inflammation. Understanding the molecular mechanisms underlying immune memory's impact on cardiac processes could lead to new therapeutic strategies to mitigate cardiovascular diseases, such as atherosclerosis, heart failure, and diabetes. These insights build the grounds for future research to balance the benefits of trained immunity with its potential risks in cardiovascular disease management.
    Keywords:  Atherosclerosis; Epigenetics; Immune memory; Trained immunity; Vaccine
    DOI:  https://doi.org/10.1007/s11886-024-02167-7
  4. BMC Microbiol. 2025 Jan 11. 25(1): 12
    Phagocytosis by macrophages decreases the radiance of bioluminescent Staphylococcus aureus.
    Elles C Boonstra, Liliana Agresti, Henny C van der Mei, Paul C Jutte, Jelmer Sjollema.
       BACKGROUND: In vivo evaluations of the antimicrobial efficacy of biomaterials often use bioluminescent imaging modalities based on bioluminescent bacteria to allow follow-up in single animals. Bioluminescence production by bacteria is dependent on their metabolic activity. It is well known that several factors can influence the metabolism of bacteria, such as the use of antimicrobials and changes in bacterial growth phase. However, little is known about the influence of intracellular residence of bacteria on bioluminescence. For example, Staphylococcus aureus can survive in the peri-implant tissue and is known to survive intracellularly in macrophages.
    RESULTS: In this study, we evaluated the bioluminescent radiance of S. aureus upon phagocytosis by macrophages. We showed that S. aureus reduced its bioluminescence upon phagocytosis by macrophages compared to S. aureus in a single culture. Simultaneously, bacterial numbers as measured by colony-forming units remained constant over time. S. aureus was released extracellularly as a result of macrophage cell death. Following this release, the bacteria increased their bioluminescence again. Replenishment of fresh macrophages showed an immediate increase in bioluminescence. Moreover, the addition of fresh macrophages showed a diminished decrease in bioluminescence at 24 h of coculture, but this effect did not last.
    CONCLUSION: Together, this study demonstrates that phagocytosis by macrophages decreases bioluminescence of S. aureus, which is an important factor to consider when using bioluminescent imaging to study the infection process in an in vivo model.
    Keywords:   In vivo imaging; Coculture of bacteria and mammalian cells; Host-Pathogen interaction; Host-defense; Immune evasion; Infections; Intracellular survival; Persistence
    DOI:  https://doi.org/10.1186/s12866-024-03674-x
  5. Nat Commun. 2025 Jan 13. 16(1): 302
    The mutational landscape of Staphylococcus aureus during colonisation.
    Francesc Coll, Beth Blane, Katherine L Bellis, Marta Matuszewska, Toska Wonfor, Dorota Jamrozy, Michelle S Toleman, Joan A Geoghegan, Julian Parkhill, Ruth C Massey, Sharon J Peacock, Ewan M Harrison.
      Staphylococcus aureus is an important human pathogen and a commensal of the human nose and skin. Survival and persistence during colonisation are likely major drivers of S. aureus evolution. Here we applied a genome-wide mutation enrichment approach to a genomic dataset of 3060 S. aureus colonization isolates from 791 individuals. Despite limited within-host genetic diversity, we observed an excess of protein-altering mutations in metabolic genes, in regulators of quorum-sensing (agrA and agrC) and in known antibiotic targets (fusA, pbp2, dfrA and ileS). We demonstrated the phenotypic effect of multiple adaptive mutations in vitro, including changes in haemolytic activity, antibiotic susceptibility, and metabolite utilisation. Nitrogen metabolism showed the strongest evidence of adaptation, with the assimilatory nitrite reductase (nasD) and urease (ureG) showing the highest mutational enrichment. We identified a nasD natural mutant with enhanced growth under urea as the sole nitrogen source. Inclusion of 4090 additional isolate genomes from 731 individuals revealed eight more genes including sasA/sraP, darA/pstA, and rsbU with signals of adaptive variation that warrant further characterisation. Our study provides a comprehensive picture of the heterogeneity of S. aureus adaptive changes during colonisation, and a robust methodological approach applicable to study in host adaptive evolution in other bacterial pathogens.
    DOI:  https://doi.org/10.1038/s41467-024-55186-x
  6. Trends Microbiol. 2025 Jan 14. pii: S0966-842X(24)00326-3. [Epub ahead of print]
    Nasal microbiota transplantation: a gateway to novel treatments.
    Sudhanshu Shekhar, Martin Schwarzer, Achal Dhariwal, Fernanda Cristina Petersen.
      Two recent studies have highlighted the potential of nasal microbiota transplantation (NMT) to treat chronic rhinosinusitis (CRS). Here we evaluate these findings and propose that lessons from fecal microbiota transplantation (FMT) could guide NMT development, with possible implications for combating antimicrobial resistance in respiratory infections.
    Keywords:  NMT; antimicrobial resistance; chronic rhinosinusitis; dysbiosis; nasal microbiota
    DOI:  https://doi.org/10.1016/j.tim.2024.12.010
  7. Cell Rep. 2025 Jan 16. pii: S2211-1247(24)01567-5. [Epub ahead of print]44(1): 115216
    Plasticity of cell death pathways ensures GSDMD activation during Yersinia pseudotuberculosis infection.
    Felicia Hui Min Chan, Hui Wen Yeap, Zonghan Liu, Safwah Nasuha Rosli, Kay En Low, Isabelle Bonne, Yixuan Wu, Shu Zhen Chong, Kaiwen W Chen.
      Macrophages express pattern recognition and cytokine receptors that mediate proinflammatory signal transduction pathways to combat microbial infection. To retaliate against such responses, pathogenic microorganisms have evolved multiple strategies to impede innate immune signaling. Recent studies demonstrated that YopJ suppression of TAK1 signaling during Yersinia pseudotuberculosis infection promotes the assembly of a RIPK1-dependent death-inducing complex that enables caspase-8 to directly cleave and activate gasdermin D (GSDMD). However, whether and how macrophages respond to Yersinia infection in the absence of YopJ or caspase-8 activity remains unclear. Here, we demonstrate that loss of YopJ or its catalytic activity triggers non-canonical inflammasome activation in macrophages and that caspase-11 is required to restrict the bacterial burden in vivo. Under conditions of low caspase-8 activity, wild-type Y. pseudotuberculosis invades macrophages and accesses the cytosol, leading to non-canonical inflammasome activation. Thus, our study highlights the plasticity of death pathways to ensure GSDMD activation during Yersinia infection.
    Keywords:  CP: Cell biology; CP: Immunology; CP: Microbiology; RIPK1; Yersinia; apoptosis; caspase-1; caspase-11; caspase-8; cell death; gasdermin; inflammasome; pyroptosis
    DOI:  https://doi.org/10.1016/j.celrep.2024.115216
  8. Sci Rep. 2025 Jan 15. 15(1): 2059
    Ticam2 ablation facilitates monocyte exhaustion recovery after sepsis.
    Blake A Caldwell, Susanti Ie, Amy Lucas, Liwu Li.
      Sepsis is a leading cause of death worldwide, with most patient mortality stemming from lingering immunosuppression in sepsis survivors. This is due in part to immune dysfunction resulting from monocyte exhaustion, a phenotype of reduced antigen presentation, altered CD14/CD16 inflammatory subtypes, and disrupted cytokine production. Whereas previous research demonstrated improved sepsis survival in Ticam2-/- mice, the contribution of TICAM2 to long-term exhaustion memory remained unknown. Using a cecal slurry injection sepsis model, we monitored the establishment and recovery of monocyte exhaustion in Ticam2-/- mice. After one week of recovery, we profiled bone marrow and splenic reservoir monocytes in Ticam2-/- mice and found that, in contrast to the persistent exhaustion observed in wild-type monocytes, Ticam2-/- monocytes largely resembled healthy controls. To determine the impact of TICAM2 ablation on innate epigenetic memory in sepsis, we measured genome-wide DNA methylation in bone marrow monocytes and found that Ticam2-/- cells exhibit a unique profile of altered methylation at CEBPE binding sites and regulatory features for key immune genes such as Dmkn and Btg1. Bearing human translational relevance, a case study of time course blood samples collected from a sepsis patient presenting with SIRS and a positive qSOFA revealed a similar effect in human monocytes, which steadily transition into an exhausted memory characterized by a CD38high; CX3CR1low; HLA-DRlow state within four days of hospital admittance. Together, our data reveal the chronic preservation of monocyte exhaustion, partially controlled by TICAM2.
    Keywords:  Innate immune memory; Monocyte exhaustion; Sepsis; Ticam2
    DOI:  https://doi.org/10.1038/s41598-025-86103-x
  9. Curr Osteoporos Rep. 2025 Jan 14. 23(1): 6
    DAMPs, PAMPs, NLRs, RIGs, CLRs and TLRs - Understanding the Alphabet Soup in the Context of Bone Biology.
    K A Carroll, M Sawden, S Sharma.
       PURPOSE OF REVIEW: The purpose of this review is to summarize the current understanding of cell-autonomous innate immune pathways that contribute to bone homeostasis and disease.
    RECENT FINDINGS: Germ-line encoded pattern recognition receptors (PRRs) are the first line of defense against danger and infections. In the bone microenvironment, PRRs and downstream signaling pathways, that mount immune defense, interface intimately with the core cellular processes in bone cells to alter bone formation and resorption. The role of PRR engagement on bone remodeling has been best described as a result of activated macrophages secreting effector molecules that reshape the characteristics of bone-resident cells. However, it is being increasingly recognized that local bone resident-cells like osteoclasts and osteoblasts possess an arsenal of PRRs. The engagement of these PRRs by stimuli in the bone niche can drive cell-autonomous (aka cell-intrinsic) responses that, in turn, impact bone-remodeling dramatically, irrespective of immune cell effectors. Indeed, this vital role for cell-autonomous innate immune responses is evident in how reduced PRR activity within osteoclast progenitors correlates with their reduced differentiation and abnormal bone remodeling. Further, cell-intrinsic PRR activity has now been shown to influence the behavior of osteoblasts, osteocytes and other local immune/non-immune cell populations. However, distinct PRR families have varying impact on bone homeostasis and inflammation, emphasizing the importance of investigating these different nodes of innate immune signaling in bone cells to better identify how they synergistically and/or antagonistically regulate bone remodeling in the course of an immune response. Innate immune sensing within bone resident cells is a critical determinant for bone remodeling in health and disease.
    DOI:  https://doi.org/10.1007/s11914-024-00900-3
  10. Bioeng Transl Med. 2025 Jan;10(1): e10715
    A stretchable human lung-on-chip model of alveolar inflammation for evaluating anti-inflammatory drug response.
    Clémentine Richter, Lorenz Latta, Daria Harig, Patrick Carius, Janick D Stucki, Nina Hobi, Andreas Hugi, Paul Schumacher, Tobias Krebs, Alexander Gamrekeli, Felix Stöckle, Klaus Urbschat, Galia Montalvo, Franziska Lautenschläger, Brigitta Loretz, Alberto Hidalgo, Nicole Schneider-Daum, Claus-Michael Lehr.
      This study describes a complex human in vitro model for evaluating anti-inflammatory drug response in the alveoli that may contribute to the reduction of animal testing in the pre-clinical stage of drug development. The model is based on the human alveolar epithelial cell line Arlo co-cultured with macrophages differentiated from the THP-1 cell line, creating a physiological biological microenvironment. To mimic the three-dimensional architecture and dynamic expansion and relaxation of the air-blood-barrier, they are grown on a stretchable microphysiological lung-on-chip. For validating the in vitro model, three different protocols have been developed to demonstrate the clinically established anti-inflammatory effect of glucocorticoids to reduce certain inflammatory markers after different pro-inflammatory stimuli: (1) an inflammation caused by bacterial LPS (lipopolysaccharides) to simulate an LPS-induced acute lung injury measured best with cytokine IL-6 release; (2) an inflammation caused by LPS at ALI (air-liquid interface) to investigate aerosolized anti-inflammatory treatment, measured with chemokine IL-8 release; and (3) an inflammation with a combination of human inflammatory cytokines TNFα and IFNγ to simulate a critical cytokine storm leading to epithelial barrier disruption, where the eventual weakening or protection of the epithelial barrier can be measured. In all cases, the presence of macrophages appeared to be crucial to mediating inflammatory changes in the alveolar epithelium. LPS induction led to inflammatory changes independently of stretch conditions. Dynamic stretch, emulating breathing-like mechanics, was essential for in vitro modeling of the clinically relevant outcome of epithelial barrier disruption upon TNFα/IFNγ-induced inflammation.
    Keywords:  3R; acute lung injury; aerosolization; cytokine storm; immuno‐competent; lung‐on‐chip; microfluidic
    DOI:  https://doi.org/10.1002/btm2.10715
  11. Nat Rev Immunol. 2025 Jan 14.
    Gasdermin pores on extracellular vesicles spread cell death.
    Alexandra Flemming.
      
    DOI:  https://doi.org/10.1038/s41577-025-01133-w
  12. PLoS One. 2025 ;20(1): e0316460
    Nasal microbiota predictors for methicillin resistant Staphylococcus colonization in critically ill children.
    Kathleen Zani, Joseph Hobeika, Yilun Sun, Christina Kohler, Anju Cherian, Trinity Fields, Qidong Jia, Li Tang, Nicholas D Hysmith, Elisa B Margolis.
       BACKGROUND: Surveillance cultures to identify patients colonized with methicillin-resistant Staphylococcus aureus (MRSA) is recommended at pediatric intensive care unit (PICU) admission but doesn't capture other methicillin-resistant Staphylococcus and is resource intensive. We determined the prevalence and identified nasal microbiome predictors for methicillin-resistant Staphylococcus colonization at the time of PICU admission.
    STUDY DESIGN: A prospective cohort study was performed in a 20-bed pediatric intensive care unit (PICU) between 2020-2021. Anterior nares nasal swabs processed for MRSA culture, nasal microbiome and mecA+ qPCR were obtained within first five days after PICU admission. Predictive values of methicillin-resistant Staphylococcus carriage on symptoms of infection and for nasal microbiome attributes were calculated.
    RESULTS: A total of 5 (8.0%) of 62 patients had a nares culture positive for MRSA and 22 (35.5%) of 63 patients had methicillin-resistant Staphylococcus (MRSA or methicillin-resistant coagulase-negative Staphylococci). In univariate analysis, carriage with MRSA or MRCoNS was associated with having a fever during PICU stay. Colonization with a distinct set of microbes (including Haemophilus, Streptococcus, Prevotella and Corynebacterium sp.) was predictive of having methicillin-resistant Staphylococcus colonization.
    CONCLUSIONS: Carriage with methicillin-resistant Staphylococcus may lead to transmission in critically ill pediatric patients. Carriage of particular nasal microbes appears to facilitate colonization with methicillin-resistant Staphylococcus.
    DOI:  https://doi.org/10.1371/journal.pone.0316460
  13. Cell Rep. 2025 Jan 10. pii: S2211-1247(24)01557-2. [Epub ahead of print]44(1): 115206
    Tumor-induced metabolic immunosuppression: Mechanisms and therapeutic targets.
    Jean-Ehrland Ricci.
      Metabolic reprogramming in both immune and cancer cells plays a crucial role in the antitumor immune response. Recent studies indicate that cancer metabolism not only sustains carcinogenesis and survival via altered signaling but also modulates immune cell function. Metabolic crosstalk within the tumor microenvironment results in nutrient competition and acidosis, thereby hindering immune cell functionality. Interestingly, immune cells also undergo metabolic reprogramming that enables their proliferation, differentiation, and effector functions. This review highlights the regulation of antitumor immune responses through metabolic reprogramming in cancer and immune cells and explores therapeutic strategies that target these metabolic pathways in cancer immunotherapy, including using chimeric antigen receptor (CAR)-T cells. We discuss innovative combinations of immunotherapy, cellular therapies, and metabolic interventions that could optimize the efficacy of existing treatment protocols.
    Keywords:  CP: Cancer; CP: Metabolism; antitumor activity of immune cells; cancer; metabolism; therapeutic strategies; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2024.115206
  14. Inflamm Res. 2025 Jan 16. 74(1): 20
    IL-8 promotes pyroptosis through ERK pathway and mediates glucocorticoid resistance in chronic rhinosinusitis with nasal polyps.
    Wei Zhang, Yun Lei, Ting Zhang, Bo You, Jie Zhang, Yong Zhou, Shaocong Zhang, Xueru Li, Yuting Liu, Lianqin Shen, Jianmei Zhao, Jing Chen.
       OBJECTIVE: This study seeks to elucidate the role and molecular mechanisms of IL-8 in nasal epithelial cell pyroptosis and its impact on glucocorticoid (GC) resistance.
    METHODS: We assessed the expression of pyroptosis-related biomarkers and IL-8 in tissues and human nasal epithelial cells (hNECs) from both control and nasal polyp patients using western blot. Their localization was determined through immunohistochemistry and immunofluorescence. Cell death and cytotoxicity assay, electron microscopy, ELISA, and immunofluorescence were utilized to investigate IL-8-induced pyroptosis and GC resistance in hNECs, alongside the examination of the involved signaling pathways via western blot and immunofluorescence. In a murine model, hematoxylin-eosin staining and immunohistochemistry clarified relationship between pyroptosis and GC resistance.
    RESULTS: IL-8 and pyroptotic biomarker expression were significantly higher in nasal polyp-derived tissues and hNECs compared to controls. IL-8 showed a positive correlation and co-localized with the pyroptotic biomarkers. IL-8 triggered pyroptosis in hNECs by activating the ERK signaling pathway, leading to increased IL-1β and IL-18 secretion. Moreover, IL-8-induced pyroptosis was found to contribute to GC resistance by affecting phosphorylation of GC receptor Ser211. Inhibition of pyroptotic proteins mitigated IL-8-induced GC resistance both in vitro and in vivo.
    CONCLUSION: Elevated IL-8 facilitates pyroptosis via the ERK signaling pathway and plays a significant role in GC resistance in nasal polyps.
    Keywords:  Epithelial cells; Glucocorticoid resistance; IL-8; Pyroptosis
    DOI:  https://doi.org/10.1007/s00011-024-01982-6
  15. iScience. 2025 Jan 17. 28(1): 111581
    TRIF-TAK1 signaling suppresses caspase-8/3-mediated GSDMD/E activation and pyroptosis in influenza A virus-infected airway epithelial cells.
    Yuling Sun, Huidi Yu, Zhihao Zhan, Wei Liu, Penggang Liu, Jing Sun, Pinghu Zhang, Xiaoquan Wang, Xiufan Liu, Xiulong Xu.
      Pyroptosis plays an important role in attracting innate immune cells to eliminate infected niches. Our study focuses on how influenza A virus (IAV) infection triggers pyroptosis in respiratory epithelial cells. Here, we report that IAV infection induces pyroptosis in a human and murine airway epithelial cell line. Mechanistically, IAV infection activates caspase-8 and caspase-3, which cleave and activate gasdermin (GSDM) D and GSDME, respectively. Z-nucleic acid-binding protein 1 (ZBP1) and receptor-interacting protein kinase (RIPK) 1 activity but not RIPK3 are required for caspase-8/3 and GSDMD/E activation and pyroptosis. GSDMD/E, ZBP1, and RIPK1 knockout all block IAV-induced pyroptosis but enhance virus replication. Transforming growth factor β-activated kinase 1 (TAK1) activation via the adaptor protein TRIF suppresses RIPK1, caspase-8/3, and GSDMD/E activation and pyroptosis. The TAK1 inhibitor 5Z-oxzeneonal (5Z) enhances IAV-induced caspase-8/3 and GSDMD/E cleavage in the lung tissues of IAV-infected mice. Our study unveils a previously unrecognized mechanism of regulation of IAV-induced pyroptosis in respiratory epithelial cells.
    Keywords:  cell biology; integrative aspects of cell biology; model organism; molecular network; virology
    DOI:  https://doi.org/10.1016/j.isci.2024.111581
  16. Int J Mol Sci. 2025 Jan 01. pii: 311. [Epub ahead of print]26(1):
    Macrophage Polarization: Learning to Manage It 3.0.
    Nadia Lampiasi.
      Macrophages are cells of the innate immune system with very peculiar characteristics, so plastic that they respond rapidly to environmental changes by assuming different and sometimes contrasting functions, such as initiating a physiological inflammatory response or interrupting it and repairing damaged tissues [...].
    DOI:  https://doi.org/10.3390/ijms26010311
  17. Cell Rep. 2025 Jan 15. pii: S2211-1247(24)01570-5. [Epub ahead of print]44(1): 115219
    Menin orchestrates macrophage reprogramming to maintain the pulmonary immune homeostasis.
    Xingwen Zhu, Bin Xu, Aobo Lian, Xiaoqian Zhang, Yiting Wang, Yuan Zhang, Li Zhang, Jie Ma, Shubin Gao, Guanghui Jin.
      Menin is a scaffold protein encoded by the Men1 gene, and it interacts with a variety of chromatin regulators to activate or repress cellular processes. The potential importance of menin in immune regulation remains unclear. Here, we report that myeloid deletion of Men1 results in the development of spontaneous pulmonary alveolar proteinosis (PAP). This is strongly correlated with impaired development of alveolar macrophages (AM) through inactivation of the granulocyte-macrophage colony-stimulating factor (GM-CSF/CSF2) pathway caused by Men1 deficiency. Mechanistically, menin directly interacts with the SET domain containing 2 (SETD2) through the N-terminal domain (NTD) and Palm domains to maintain protein stability and chromatin recruitment. SETD2 and menin collectively maintain CSF2 expression through H3K36me3, which orchestrates AM reprogramming and pulmonary immune homeostasis. Targeting H3K36me3 remodeling mitigated the aberrant activation of macrophages caused by lipopolysaccharide (LPS). Our results point to a nonredundant role of menin in the control of macrophage lineage maintenance via reinforcement of the H3K36me3 transcriptional program.
    Keywords:  CP: Immunology; CSF2; Men1; SETD2; alveolar macrophages; pulmonary alveolar proteinosis
    DOI:  https://doi.org/10.1016/j.celrep.2024.115219
  18. Adv Sci (Weinh). 2025 Jan 14. e2411233
    A Multicellular In Vitro Model of the Human Intestine with Immunocompetent Features Highlights Host-Pathogen Interactions During Early Salmonella Typhimurium Infection.
    Spyridon Damigos, Aylin Caliskan, Gisela Wajant, Sara Giddins, Adriana Moldovan, Sabine Kuhn, Evelyn Putz, Thomas Dandekar, Thomas Rudel, Alexander J Westermann, Daniela Zdzieblo.
      Studying the molecular basis of intestinal infections caused by enteric pathogens at the tissue level is challenging, because most human intestinal infection models have limitations, and results obtained from animals may not reflect the human situation. Infections with Salmonella enterica serovar Typhimurium (STm) have different outcomes between organisms. 3D tissue modeling of primary human material provides alternatives to animal experimentation, but epithelial co-culture with immune cells remains difficult. Macrophages, for instance, contribute to the immunocompetence of native tissue, yet their incorporation into human epithelial tissue models is challenging. A 3D immunocompetent tissue model of the human small intestine based on decellularized submucosa enriched with monocyte-derived macrophages (MDM) is established. The multicellular model recapitulated in vivo-like cellular diversity, especially the induction of GP2 positive microfold (M) cells. Infection studies with STm reveal that the pathogen physically interacts with these M-like cells. MDMs show trans-epithelial migration and phagocytosed STm within the model and the levels of inflammatory cytokines are induced upon STm infection. Infected epithelial cells are shed into the supernatant, potentially reflecting an intracellular reservoir of invasion-primed STm. Together, the 3D model of the human intestinal epithelium bears potential as an alternative to animals to identify human-specific processes underlying enteric bacterial infections.
    Keywords:   Salmonella enterica serovar Typhimurium; host‐pathogen interaction; human in vitro infection models; immunocompetent models; intestinal tissue models; microfold cells; organoids
    DOI:  https://doi.org/10.1002/advs.202411233
  19. Nature. 2025 Jan 10.
    These are the 20 most-studied bacteria - the majority have been ignored.
    Ewen Callaway.
      
    Keywords:  Microbiology
    DOI:  https://doi.org/10.1038/d41586-025-00038-x
  20. Int J Mol Sci. 2025 Jan 05. pii: 407. [Epub ahead of print]26(1):
    Alveolar Macrophages in Viral Respiratory Infections: Sentinels and Saboteurs of Lung Defense.
    Pauline Pöpperl, Melanie Stoff, Andreas Beineke.
      Respiratory viral infections continue to cause pandemic and epidemic outbreaks in humans and animals. Under steady-state conditions, alveolar macrophages (AlvMϕ) fulfill a multitude of tasks in order to maintain tissue homeostasis. Due to their anatomic localization within the deep lung, AlvMϕ are prone to detect and react to inhaled viruses and thus play a role in the early pathogenesis of several respiratory viral infections. Here, detection of viral pathogens causes diverse antiviral and proinflammatory reactions. This fact not only makes them promising research targets, but also suggests them as potential targets for therapeutic and prophylactic approaches. This review aims to give a comprehensive overview of the current knowledge about the role of AlvMϕ in respiratory viral infections of humans and animals.
    Keywords:  SARS-CoV-2; alveolar macrophages; influenza A virus; innate immunity; respiratory infection; respiratory syncytial virus; tissue-resident macrophages
    DOI:  https://doi.org/10.3390/ijms26010407
  21. Inflammation. 2025 Jan 13.
    Inhibition of Mitochondrial Succinate Dehydrogenase with Dimethyl Malonate Promotes M2 Macrophage Polarization by Enhancing STAT6 Activation.
    Chaowen He, Pengfei Chen, Luwen Ning, Xiuping Huang, Huimin Sun, Yuanyuan Wang, Yanli Zhao, Changchun Zeng, Dongsheng Huang, Hanchao Gao, Mengtao Cao.
      Macrophages exhibit diverse phenotypes depending on environment status, which contribute to physiological and pathological processes of immunological diseases, including sepsis, asthma, multiple sclerosis and colitis. The alternative activation of macrophages is tightly regulated to avoid excessive activation and damage of tissues and organs. Certain works characterized that succinate dehydrogenase (SDH) altered function of macrophages and promoted inflammatory response in M1 macrophages via mitochondrial reactive oxygen species (ROS). However, the effect of succinate dehydrogenase on M2 macrophage polarization remains incompletely understood. We employed dimethyl malonate (DMM) to inhibit succinate dehydrogenase activity and took use of RNA-seq to analyze the changes of inflammatory response of LPS-activated M1 macrophages or IL 4-activated M2 macrophages. Our data revealed that inhibition of SDH with DMM increased expression of M2 macrophages-associated signature genes, including Arg1, Ym1 and Mrc1. Consistent with previous work, we also observed that inhibition of SDH decreased the expression of IL-1β and enhanced the levels of IL-10 in M1 macrophages. Additionally, inhibition of SDH with DMM inhibited the production of chemokines, such as Cxcl3, Cxcl12, Ccl20 and Ccl9. DMM also amplified the M2 macrophages-related signature genes in IL-13-activated M2 macrophages. Mechanistic studies revealed that DMM promoted M2 macrophages polarization through mitochondrial ROS dependent STAT6 activation. Blocking ROS with mitoTEMPO or inhibiting STAT6 activation with ruxolitinib abrogated the promotion effect of DMM on M2 macrophages. Finally, dimethyl malonate treatment promoted peritoneal M2 macrophages differentiation and exacerbated OVA-induced allergy asthma in vivo. Collectively, we identified SDH as a braker to suppress M2 macrophage polarization via mitochondrial ROS, suggesting a novel strategy to treatment of M2 macrophages-mediated inflammatory diseases.
    Keywords:  Asthma; JAK-STAT6 pathway; M2 macrophage polarization; Succinate dehydrogenase
    DOI:  https://doi.org/10.1007/s10753-024-02207-y
  22. Electrophoresis. 2025 Jan 12.
    Spatio-Temporal Change of Skin and Oral Microbiota: A Longitudinal Study of Microbial Diversity and Stability.
    Han Zhang, Anqi Chen, Shilin Li, Kaiqin Chen, Xuechun You, Yingnan Bian, Chengtao Li, Shiquan Liu, Jiang Huang, Suhua Zhang.
      The human skin and oral cavity harbor complex microbial communities, which exist in dynamic equilibrium with the host's physiological state and the external environment. This study investigates the microbial atlas of human skin and oral cavities using samples collected over a 10-month period, aiming to assess how both internal and external factors influence the human microbiome. We examined bacterial community diversity and stability across various body sites, including palm and nasal skin, saliva, and oral epithelial cells, during environmental changes and a COVID-19 pandemic. The skin microbiome was confirmed to display spatial and temporal stability compared to the oral microbiome, particularly the oral epithelium, which was susceptible to changes in the host's physiological state and immune response. Moreover, significant differences in the microbial community structure among the 4 sample types were observed, and 87 distinct bacteria biomarkers were identified. The random forest prediction model achieved an overall prediction accuracy of 95.24% across the four types of samples studied. Additionally, nasal skin samples showed significant promise for individual identification through profiling the skin microbiota. These findings highlight the potential of skin and oral microbiota as forensic markers for inferring body sites and identifying individuals. In summary, despite facing limitations such as a small cohort size and the need for broader validation, this research provides an overall perspective and initial insights for refining experimental designs and conducting in-depth research in various microbial research fields.
    Keywords:  16S rRNA; microbiota; oral; skin; spatio‐temporal variation
    DOI:  https://doi.org/10.1002/elps.202400160
  23. Int J Mol Sci. 2024 Dec 24. pii: 27. [Epub ahead of print]26(1):
    Regulatory Roles of Noncanonical Inflammasomes in Inflammatory Lung Diseases.
    Young-Su Yi.
      The inflammatory response consists of two stages: priming and triggering. The triggering stage is marked by the activation of inflammasomes, which are cytosolic protein complexes acting as platforms for inflammation. Inflammasomes are divided into canonical and noncanonical categories. Inflammatory lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), inflammatory lung injury, and pulmonary fibrosis arise from lung inflammation and damage. While the role of canonical inflammasomes in these diseases is well demonstrated, recent findings emphasize the critical roles of noncanonical inflammasomes in regulating inflammation and various inflammatory conditions. Particularly, new studies highlight their involvement in inflammatory lung diseases. This review delves into recent research on the regulatory roles of noncanonical inflammasomes, such as human caspase-4 and murine caspase-11, in lung inflammation and the development of inflammatory lung diseases, as well as the potential for targeting these inflammasomes for new treatments.
    Keywords:  caspase-11; caspase-4; inflammation; lung disease; noncanonical inflammasome
    DOI:  https://doi.org/10.3390/ijms26010027
  24. Dermatitis. 2025 Jan 13.
    Pathogenic Colonization: Defining the Role of Staphylococcus aureus in Atopic Dermatitis.
    Kripa Ahuja, Meghana Sunkara, Peter Lio.
      
    DOI:  https://doi.org/10.1089/derm.2024.0401
  25. Sci Adv. 2025 Jan 17. 11(3): eadq8158
    Single-cell analysis reveals Mycobacterium tuberculosis ESX-1-mediated accumulation of permissive macrophages in infected mouse lungs.
    Weihao Zheng, Michael Borja, Leah C Dorman, Jonathan Liu, Andy Zhou, Amanda Seng, Ritwicq Arjyal, Sara Sunshine, Alina Nalyvayko, Angela Oliveira Pisco, Oren S Rosenberg, Norma Neff, Beth Shoshana Zha.
      Mycobacterium tuberculosis (MTB) ESX-1, a type VII secretion system, is a key virulence determinant contributing to MTB's survival within lung mononuclear phagocytes (MNPs), but its effect on MNP recruitment and differentiation remains unknown. Here, using multiple single-cell RNA sequencing techniques, we studied the role of ESX-1 in MNP heterogeneity and response in mice and murine bone marrow-derived macrophages (BMDM). We found that ESX-1 is required for MTB to recruit diverse MNP subsets with high MTB burden. Further, MTB induces a transcriptional signature of immune evasion in lung macrophages and BMDM in an ESX-1-dependent manner. Spatial transcriptomics revealed an up-regulation of permissive features within MTB lesions, where monocyte-derived macrophages concentrate near MTB-infected cells. Together, our findings suggest that MTB ESX-1 facilitates the recruitment and differentiation of MNPs, which MTB can infect and manipulate for survival. Our dataset across various models and methods could contribute to the broader understanding of recruited cell heterogeneity during MTB lung infection.
    DOI:  https://doi.org/10.1126/sciadv.adq8158
  26. J Invest Dermatol. 2025 Jan 08. pii: S0022-202X(24)03024-0. [Epub ahead of print]
    Ferroptosis: A Targetable Vulnerability for Melanoma Treatment.
    Yu Meng, Qian Zhou, Yating Dian, Furong Zeng, Guangtong Deng, Xiang Chen.
      Melanoma is a devastating form of skin cancer characterized by a high mutational burden, limited treatment success, and dismal prognosis. Although immunotherapy and targeted therapies have significantly revolutionized melanoma treatment, the majority of patients fail to achieve durable responses, highlighting the urgent need for novel therapeutic strategies. Ferroptosis, an iron-dependent form of regulated cell death driven by the overwhelming accumulation of lipid peroxides, has emerged as a promising therapeutic approach in preclinical melanoma models. A deeper understanding of the ferroptosis landscape in melanoma based on its biology characteristics, including phenotypic plasticity, metabolic state, genomic alterations, and epigenetic changes, as well as the complex role and mechanisms of ferroptosis in immune cells could provide a foundation for developing effective treatments. In this review, we outline the molecular mechanisms of ferroptosis, decipher the role of melanoma biology in ferroptosis regulation, reveal the therapeutic potential of ferroptosis in melanoma, and discuss the pressing questions that should guide future investigations into ferroptosis in melanoma.
    Keywords:  Ferroptosis; Immune; Melanoma; Metabolism
    DOI:  https://doi.org/10.1016/j.jid.2024.11.007
  27. Immune Netw. 2024 Dec;24(6): e41
    Bifidobacterium longum RAPO Attenuates Dermal and Pulmonary Fibrosis in a Mouse Model of Systemic Sclerosis through Macrophage Modulation and Growth of Short-Chain Fatty Acid Producers.
    Hee Jin Park, Dakyum Yu, Seong-Tshool Hong, Juyeon Lee, Sang-Jun Park, Myeong Soo Park, Hanna Lee, Mingyo Kim, Yun-Hong Cheon, Seung-Geun Lee, Dong Hyun Sohn, Jae-Bum Jun, Suhee Kim, Sang-Il Lee.
      Systemic sclerosis (SSc) is a complex autoimmune disease with an unclear etiology and no effective treatments. Recent research has suggested involvement of the microbiome in SSc pathogenesis. This study aimed to identify specific microbial species associated with SSc and explore their therapeutic potential. Serum Abs against 384 intestinal microbial species revealed a significant depletion in Abs against Bifidobacterium longum in patients with SSc compared to healthy controls. In a bleomycin-induced SSc mouse model, oral administration of B. longum strain RAPO attenuated skin and lung fibrosis, accompanied by reduced infiltration of inflammatory monocytes/macrophages and downregulation of pro-inflammatory cytokines and chemoattractant Ccl2 genes in lymph nodes and fibrotic tissues. B. longum RAPO treatment restored fecal microbial diversity and augmented short-chain fatty acid (SCFA)-producing bacteria in the gut, leading to increased fecal butyrate levels and upregulated SCFA receptor Gpr41 in the mesenteric lymph node. In vitro, B. longum RAPO and its culture supernatant suppressed the expressions of pro-inflammatory cytokine genes in macrophages and inhibited myofibroblast differentiation in fibroblasts. These findings highlight the probiotic potential of B. longum RAPO in preventing tissue fibrosis by modulating macrophage activity and promoting the growth of SCFA-producing bacteria, underscoring the therapeutic potential of microbial modulation in SSc.
    Keywords:  Bacterial antibodies; Bifidobacterium longum; Fibrosis; Short-chain fatty acid; Systemic sclerosis
    DOI:  https://doi.org/10.4110/in.2024.24.e41
  28. Trends Cancer. 2025 Jan 09. pii: S2405-8033(24)00288-7. [Epub ahead of print]
    Recent developments in myeloid immune modulation in cancer therapy.
    Sepideh Parvanian, Xinying Ge, Christopher S Garris.
      Myeloid cells play a crucial dual role in cancer progression and response to therapy, promoting tumor growth, enabling immune suppression, and contributing to metastatic spread. The ability of these cells to modulate the immune system has made them attractive targets for therapeutic strategies aimed at shifting their function from tumor promotion to fostering antitumor immunity. Therapeutic approaches targeting myeloid cells focus on modifying their numbers, genetics, metabolism, and interactions within the tumor microenvironment. These strategies aim to reverse their suppressive functions and redirect them to support antitumor immune responses by inhibiting immunosuppressive pathways, targeting specific receptors, and promoting their differentiation into less immunosuppressive phenotypes. Here, we discuss recent approaches to clinically target tumor myeloid cells, focusing on reprogramming myeloid cells to promote antitumor immunity.
    Keywords:  cancer immunotherapy; dendritic cell; immune agonist; macrophage; myeloid
    DOI:  https://doi.org/10.1016/j.trecan.2024.12.003
  29. J Arthroplasty. 2025 Jan 09. pii: S0883-5403(25)00001-4. [Epub ahead of print]
    Emerging Concepts in Periprosthetic Joint Infection Research: The Human Microbiome.
    Nathanael D Heckmann, McKenzie Culler, Michael A Mont, Jay R Lieberman, Javad Parvizi.
      Microorganisms, including bacteria, fungi, and viruses, that reside on and within the human body are collectively known as the human microbiome. Dysbiosis, or disruption in the microbiome, has been implicated in several disease processes, including asthma, obesity, autoimmune diseases, and numerous other conditions. While the Human Microbiome Project (HMP) and the generation of descriptive studies it inspired established correlations between characteristic patterns in the composition of the microbiome and specific disease phenotypes, current research has begun to focus on elucidating the causal role of the microbiome in disease pathogenesis. Within the field of orthopaedic surgery, researchers have proposed the concept of a "gut-joint axis" by which the intestinal microbiome influences joint health and the development of diseases such as osteoarthritis and periprosthetic joint infection (PJI). It is theorized that intestinal dysbiosis increases gut permeability, leading to the translocation of bacteria and their metabolic products into the systemic circulation and the stimulation of proinflammatory response cascades throughout the body, including within the joints. While correlative studies have identified patterns of dysbiotic derangement associated with osteoarthritis and PJI, translational research is needed to clarify the precise mechanisms by which these changes influence disease processes. Additionally, an emerging body of literature has challenged the previously held belief that certain body sites are sterile and do not possess a microbiome, with studies identifying distinct microbial genomic signatures and a core microbiome that varies between anatomic sites. A more thorough characterization of the joint microbiome may have profound implications for our understanding of PJI pathogenesis and our ability to stratify patients based on risk. The purpose of this review was to outline our current understanding of the human microbiome, to describe the gut-joint axis and its role in specific pathologies, including PJI, and to highlight the potential of microbiome-based therapeutic interventions in the field of orthopaedics.
    DOI:  https://doi.org/10.1016/j.arth.2025.01.001
  30. Inflammation. 2025 Jan 11.
    Piezo1-Induced Nasal Epithelial Barrier Dysfunction in Allergic Rhinitis.
    Shengyang Liu, Jianhua Wu, Linghui Meng, Yuan Liu, Jinzhuang Yu, Jing Yue, Dingqian Hao, Peng Yu, YuZhu Wan, Ping Li, Peng Jin, Li Shi.
      This study aimed to investigate the role of Piezo1 in nasal epithelial barrier dysfunction in allergic rhinitis (AR) using both in vitro and in vivo experimental methods. A total of 79 human nasal mucosal samples were collected, including 43 from AR patients and 36 from healthy controls. Additionally, 12 BALB/c mice were used for the in vivo experiments. Human nasal epithelial cells (HNEpCs) were employed for the in vitro studies. In the in vivo study, mice were sensitized with ovalbumin (OVA) to induce AR. In the in vitro experiments, Piezo1 expression in HNEpCs was silenced using shRNA, followed by stimulation with IL-13. The expression of Piezo1, ERK1/2, and tight junctions (TJs) components (including ZO-1, Occludin, and Claudin-1) was assessed using quantitative RT-PCR, immunofluorescence, and Western blotting. Statistical analyses included paired Student's t-test and one-way ANOVA. Piezo1 expression was significantly elevated in both AR patients and OVA-induced AR mice, while TJs components were significantly reduced (p < 0.05). Knockdown of Piezo1 in HNEpCs restored the levels of TJs and improved barrier integrity. A negative correlation between Piezo1 and ERK1/2 expression was observed. Piezo1 plays a crucial role in nasal epithelial barrier dysfunction in AR by modulating TJs and the ERK1/2 pathway. These findings suggest that Piezo1 may serve as a potential therapeutic target for AR.
    Keywords:  Allergic rhinitis; Human nasal epithelial; Piezo1; Tight junctions (TJs)
    DOI:  https://doi.org/10.1007/s10753-024-02234-9
  31. Nat Microbiol. 2025 Jan 10.
    A BCG kill switch strain protects against Mycobacterium tuberculosis in mice and non-human primates with improved safety and immunogenicity.
    Alexander A Smith, Hongwei Su, Joshua Wallach, Yao Liu, Pauline Maiello, H Jacob Borish, Caylin Winchell, Andrew W Simonson, Philana Ling Lin, Mark Rodgers, Daniel Fillmore, Jennifer Sakal, Kan Lin, Valerie Vinette, Dirk Schnappinger, Sabine Ehrt, JoAnne L Flynn.
      Improved vaccination strategies for tuberculosis are needed. Intravenous (i.v.) delivery of live attenuated Mycobacterium bovis BCG provides protection against Mycobacterium tuberculosis (Mtb) in macaques but poses safety challenges. Here we genetically engineered two strains, BCG-TetON-DL and BCG-TetOFF-DL, to either induce or inhibit expression of two phage lysin operons, respectively, upon tetracycline exposure. We show that lysin expression kills BCG in vitro, in infected macrophages, and following infection of immunocompetent (C57BL/6) and immunocompromised (SCID) mice. Modified BCG elicited similar immune responses and provided similar protection against Mtb challenge as wild-type BCG in mice. In macaques, cessation of tetracycline treatment reduced i.v.-administered BCG-TetOFF-DL numbers. Intravenous BCG-TetOFF-DL increased pulmonary CD4 T-cell responses compared with wild-type BCG-induced responses and provided robust protection against Mtb challenge. Sterilizing immunity occurred in 6 of 8 macaques compared with 2 of 8 wild-type BCG-immunized macaques. Thus, a 'kill-switch' BCG strain provides additional safety and robust protection against Mtb infection.
    DOI:  https://doi.org/10.1038/s41564-024-01895-4
  32. Trends Microbiol. 2025 Jan 10. pii: S0966-842X(24)00325-1. [Epub ahead of print]
    Emerging models to study competitive interactions within bacterial communities.
    Mollie Virgo, Serge Mostowy, Brian T Ho.
      Within both abiotic and host environments, bacteria typically exist as diverse, multispecies communities and have crucial roles in human health, agriculture, and industry. In these communities, bacteria compete for resources, and these competitive interactions can shape the overall population structure and community function. Studying bacterial community dynamics requires experimental model systems that capture the different interaction networks between bacteria and their surroundings. We examine the recent literature advancing such systems, including (i) in silico models establishing the theoretical basis for how cell-to-cell interactions can influence population level dynamics, (ii) in vitro models characterizing specific interbacterial interactions, (iii) organ-on-a-chip models revealing the physiologically relevant parameters, such as spatial structure and mechanical forces, that bacteria encounter within a host, and (iv) in vivo plant and animal models connecting the host responses to interbacterial interactions. Each of these systems has greatly contributed to our understanding of bacterial community dynamics and can be used synergistically to understand how bacterial competition influences population architecture.
    Keywords:  T6SS; bacterial communities; bacterial competition; microbiota; organ-on-chip
    DOI:  https://doi.org/10.1016/j.tim.2024.12.009
  33. Int Wound J. 2025 Jan;22(1): e70108
    Comparison of cell-scaffold interactions in a biological and a synthetic wound matrix.
    Joon Pio Hong, Joanneke Maitz, Matthias Mörgelin.
      Wound healing is a central physiological process that restores the barrier properties of the skin after injury, comprising close coordination between several cell types (including fibroblasts and macrophages) in the wound bed. The complex mechanisms involved are executed and regulated by an equally complex, reciprocal signalling network involving numerous signalling molecules such as catabolic and anabolic inflammatory mediators (e.g., cytokines, chemokines). In chronic wound environments, the balance in the molecular signatures of inflammatory mediators is usually impaired. Thus, we compared the ability of a collagen-based wound matrix against a synthetic wound matrix to attract fibroblasts and macrophages that deliver these signalling molecules. In particular, the balance between pro- and anti- inflammatory cytokine secretion was assessed. We found that the natural collagen-based matrix was the most efficient adhesive substrate to recruit and activate fibroblasts and macrophages on its surface. These cells secreted a variety of cytokines, and the natural biomaterial exhibited a more balanced secretion of pro- and anti-inflammatory mediators than the synthetic comparator. Thus, our study highlights the ability of native collagen matrices to modulate inflammatory mediator signatures in the wound bed, indicating that such devices may be beneficial for wound healing in the clinical setting.
    Keywords:  extracellular matrix; fibrillar collagens; inflammation mediators; tissue scaffolds; wound healing
    DOI:  https://doi.org/10.1111/iwj.70108
  34. J Food Sci. 2025 Jan;90(1): e17651
    Roles of oolong tea extracts in the protection against Staphylococcus aureus infection in Caenorhabditis elegans.
    Xiao Zhang, Xiaolin Meng, Yuju Liu, Ximiao Yang, Jianwen Chen, Tong Liu, Zhenlin Liao, Xiang Fang, Jie Wang.
      Oolong tea, a popular traditional Chinese tea, possesses various bioactivities, but little is known about its roles in the protection against pathogens, such as Staphylococcus aureus, in vivo. This study investigated the roles of the water-soluble oolong tea extracts (OTE) on S. aureus infection in Caenorhabditis elegans, a promising model to study the host-microbe interactions in vivo. Pretreatment with OTE (0.6% and 1.2%) and co-treatment with OTE and S. aureus extended the lifespan by 11.16%-30.37%, increased the body bends by 36.49%-101.39%, inhibited the lipid accumulation by 11.71%-35.21% and S. aureus colonization in the intestine by 5.02%-30.68%, and enhanced the mitochondrial transmembrane potential by 51.92%-74.83%, compared with the control groups where worms were fed with S. aureus. Moreover, pretreatment with OTE and co-treatment with OTE and S. aureus suppressed the production of reactive oxygen species, increased the production of glutathione and superoxide dismutases (SODs), and altered the transcripts of genes encoding SODs, glutathione-S-transferases, and antimicrobial proteins and peptides in different ways. Furthermore, pretreatment with OTE failed to extend the lifespan of the nematode mutants defective in age-1, akt-2, skn-1, or hsf-1, and co-treatment with OTE and S. aureus could not extend the lifespan of the nematode mutants defective in age-1, akt-2, sek-1, pmk-1, mpk-1, or skn-1. These findings indicated that OTE exhibited the preventive and protective effects on S. aureus infection by increasing the antioxidant properties and expression of antimicrobial proteins and peptides via insulin/IGF-1 and/or p38/ERK mitogen-activated protein kinase (MAPK) pathway and transcription factor SKN-1 and/or HSF-1, which implied OTE could be used as a potential food additive to prevent S. aureus infection. PRACTICAL APPLICATION: Staphylococcus aureus is harmful to animal and human health, such as leading to immune system disorders. This study demonstrated that oolong tea extracts could be a potential additive used in food and feeds to protect animal and human from S. aureus infection by increasing the antioxidant properties and the expression of antimicrobial proteins and peptides.
    Keywords:  Caenorhabditis elegans; Staphylococcus aureus; antioxidant properties; immune response pathways; oolong tea
    DOI:  https://doi.org/10.1111/1750-3841.17651
  35. Lancet Microbe. 2025 Jan 13. pii: S2666-5247(24)00310-0. [Epub ahead of print] 101042
    Clinical implications of maternal multikingdom transmissions and early-life microbiota.
    Shuqin Zeng, Meicen Zhou, Dezhi Mu, Shaopu Wang.
      Mother-to-infant transmission of the bacteriome, virome, mycobiome, archaeome, and their mobile genetic elements has been recognised in nature as an important step for the infant to acquire and maintain a healthy early-life (from birth till age 3 years) microbiota. A comprehensive overview of other maternal multikingdom transmissions remains unavailable, except for that of the bacteriome. Associations between microorganisms and diseases throughout the human life span have been gradually discovered; however, whether these microorganisms are maternally derived and how they concomitantly interact with other microbial counterparts remain poorly understood. This Review first discusses the current understanding of maternal multikingdom transmissions, their contributions to the development of early-life microbiota, and the primary factors that influence the transmission processes. The clinical implications of the inherited microbiota on human health in early life have been emphasised upon next, along with highlighting of knowledge gaps that should be addressed in future research. Finally, interventions to restore typical vertical transmission or disturbed early-life microbiota have been discussed as potential therapeutic approaches.
    DOI:  https://doi.org/10.1016/j.lanmic.2024.101042
  36. Res Microbiol. 2025 Jan 11. pii: S0923-2508(25)00002-6. [Epub ahead of print] 104267
    Staphylococcus aureus: Dynamics of pathogenicity and antimicrobial-resistance in hospital and community environments - Comprehensive overview.
    Giorgio Silva-Santana.
      This study reviews Staphylococcus aureus, a significant pathogen in both hospital and community-acquired infections, addressing its epidemiology, pathogenesis, and antimicrobial resistance. It highlights virulence mechanisms, such as adhesion factors, toxins, enzymes, and biofilms, which contribute to survival and immune evasion. The spread of resistance occurs through the transfer of mobile genetic elements like SCCmec and genetic mutations. The analysis also compares hospital and community strains, including multidrug-resistant lineages like MRSA, VISA, and VRSA. The study concludes that S. aureus presents a major public health challenge, requiring new therapeutic approaches and preventive strategies.
    Keywords:  Antimicrobial resistance; Biofilm; Epidemiology; Infection; Staphylococcus aureus; Virulence
    DOI:  https://doi.org/10.1016/j.resmic.2025.104267
  37. Front Antibiot. 2023 ;2 1309107
    Transient comparison of techniques to counter multi-drug resistant bacteria: prime modules in curation of bacterial infections.
    Muhammad Naveed, Muhammad Waseem, Izma Mahkdoom, Nouman Ali, Farrukh Asif, Jawad Ul Hassan, Hamza Jamil.
      Multidrug-resistant organisms are bacteria that are no longer controlled or killed by specific drugs. One of two methods causes bacteria multidrug resistance (MDR); first, these bacteria may disguise multiple cell genes coding for drug resistance to a single treatment on resistance (R) plasmids. Second, increased expression of genes coding for multidrug efflux pumps, which extrude many drugs, can cause MDR. Antibiotic resistance is a big issue since some bacteria may withstand almost all antibiotics. These bacteria can cause serious sickness, making them a public health threat. Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), Multidrug resistant Mycobacterium tuberculosis (TB), and CRE are gut bacteria that resist antibiotics. Antimicrobial resistance is rising worldwide, increasing clinical and community morbidity and mortality. Superbugs have made antibiotic resistance in some environmental niches even harder to control. This study introduces new medicinal plants, gene-editing methods, nanomaterials, and bacterial vaccines that will fight MDR bacteria in the future.
    Keywords:  bacterial vaccines; medicinal plants; multi-drug resistant bacteria; staphylococcus aureus; vancomycin-resistant enterococcus
    DOI:  https://doi.org/10.3389/frabi.2023.1309107
  38. Methods Mol Biol. 2025 Jan 17.
    Protocol for the Generation and 3D Culture of Fluorescently Labeled Multicellular Spheroids.
    Emily C Liu, Amy L Ryan, Sinem Koc-Günel.
      Spheroid culture systems have been extensively used to model the three-dimensional (3D) behavior of cells in vitro. Traditionally, spheroids consist of a single cell type, limiting their ability to fully recapitulate the complex inter-cellular interactions observed in vivo. Here we describe a protocol for generating cocultured spheroids composed of two distinct cell types, embedded within a 3D extracellular matrix (ECM) to better study cellular interactions. Fluorescent labeling of each cell type enables clear distinction and visualization, facilitating the analysis of cell invasion, proliferation, and behavior within the matrix. This method is particularly suited for studying matrix invasion, an essential process in cancer metastasis, using both fixed and live cell microscopy. The protocol is versatile and can be adapted for various cell types, providing a robust platform for investigating cell-cell interactions in cancer research, tissue remodeling, and drug screening.
    Keywords:  3D spheroids; Extracellular matrix; Fluorescence imaging; Human lung fibroblasts; Invasion; Lymphatic endothelium; Multicellular interactions
    DOI:  https://doi.org/10.1007/7651_2024_592
  39. Nat Commun. 2025 Jan 10. 16(1): 584
    Tracheal tuft cells release ATP and link innate to adaptive immunity in pneumonia.
    Noran Abdel Wadood, Monika I Hollenhorst, Mohamed Ibrahem Elhawy, Na Zhao, Clara Englisch, Saskia B Evers, Mahana Sabachvili, Stephan Maxeiner, Amanda Wyatt, Christian Herr, Ann-Kathrin Burkhart, Elmar Krause, Daniela Yildiz, Anja Beckmann, Soumya Kusumakshi, Dieter Riethmacher, Markus Bischoff, Sandra Iden, Sören L Becker, Brendan J Canning, Veit Flockerzi, Thomas Gudermann, Vladimir Chubanov, Robert Bals, Carola Meier, Ulrich Boehm, Gabriela Krasteva-Christ.
      Tracheal tuft cells shape immune responses in the airways. While some of these effects have been attributed to differential release of either acetylcholine, leukotriene C4 and/or interleukin-25 depending on the activating stimuli, tuft cell-dependent mechanisms underlying the recruitment and activation of immune cells are incompletely understood. Here we show that Pseudomonas aeruginosa infection activates mouse tuft cells, which release ATP via pannexin 1 channels. Taste signaling through the Trpm5 channel is essential for bacterial tuft cell activation and ATP release. We demonstrate that activated tuft cells recruit dendritic cells to the trachea and lung. ATP released by tuft cells initiates dendritic cell activation, phagocytosis and migration. Tuft cell stimulation also involves an adaptive immune response through recruitment of IL-17A secreting T helper cells. Collectively, the results provide a molecular framework defining tuft cell dependent regulation of both innate and adaptive immune responses in the airways to combat bacterial infection.
    DOI:  https://doi.org/10.1038/s41467-025-55936-5
  40. JID Innov. 2025 Jan;5(1): 100324
    Langerhans Cells Directly Interact with Resident T Cells in the Human Epidermis.
    Tomonori Oka, Tatsuya Hasegawa, Truelian Lee, Valeria S Oliver-Garcia, Mahsa Mortaja, Marjan Azin, Satoshi Horiba, Sabrina S Smith, Sara Khattab, Kathryn E Trerice, Steven T Chen, Yevgeniy R Semenov, Shadmehr Demehri.
      Adult human skin contains nearly twice as many T cells as the peripheral blood, which include tissue-resident memory T cells. However, the precise mechanisms maintaining tissue-resident memory T cells in the healthy skin remain unclear. Using normal human skin samples, we find that Langerhans cells (LCs) contact T cells in the epidermis of the elderly. LCs with high HLA-II, CD86, and PD-L2 expression directly contacted PD-1+ tissue-resident memory T cells and CTLA-4+ regulatory T cells in the epidermis, indicating an axis of peripheral tolerance in a steady state. Environmental insults, UVB radiation, and hapten downregulated HLA-II and CD86 on LCs in the epidermis, suggesting that disruption of LC-T cell tolerogenic axis contributes to skin inflammation. Interestingly, immune checkpoint blockade therapy was associated with decreased epidermal LC-T cell contact in the normal skin of patients with cancer affected by cutaneous immune-related adverse events. Collectively, our findings indicate that LCs may contribute to T cell tolerance in the epidermis.
    Keywords:  Immune checkpoint; Langerhans cell; Peripheral tolerance; Regulatory T cell; Tissue-resident memory T cell
    DOI:  https://doi.org/10.1016/j.xjidi.2024.100324
  41. PLoS Pathog. 2025 Jan 17. 21(1): e1012449
    Deficient neutrophil responses early in influenza infection promote viral replication and pulmonary inflammation.
    Henry H Gong, Matthew J Worley, Kyle A Carver, Caleb J Godin, Jane C Deng.
      Neutrophils play key protective roles in influenza infections, yet excessive neutrophilic inflammation is a hallmark of acute lung injury during severe infections. Phenotypic heterogeneity is increasingly recognized in neutrophil populations; however, how functional variation in neutrophils between individuals determine the diverse outcomes of influenza remains unclear. To examine immunologic responses that may drive varying outcomes in influenza, we infected C57BL/6 (B6) and A/J mice with mouse-adapted influenza A virus A/PR/8/34 H1N1. A self-resolving dose in B6 mice was lethal in A/J mice, which had increased viral load throughout infection accompanied by prominent bronchoalveolar neutrophilia and pulmonary vascular leakage preceding mortality. Notably, the B6 mice heavily recruited neutrophils to lungs early in infection while A/J mice failed to do so. Neutrophils from A/J mice additionally displayed reduced neutrophil extracellular trap (NET) release and reactive oxygen species (ROS) generation compared to B6 mice early in infection, suggesting the failure to control virus in A/J mice was a product of deficient neutrophil response. To determine if variation in neutrophils between strains governed viral control and inflammation, we adoptively transferred bone marrow neutrophils from B6 or A/J donors to A/J recipients early in infection and found that the transfer of B6 neutrophils enhanced viral clearance and abrogated the dissemination of CXCL1 and IL-6. The transfer of A/J neutrophils, however, failed to achieve either. Furthermore, B6 neutrophils were capable of greater levels of viral killing in vitro than their A/J counterparts. These results suggest that a key moderator of inflammation in influenza infection is the control of virus by neutrophils early in infection. Thus, host-specific differences in both the recruitment of these cells as well as interindividual variation in neutrophil ability to support viral clearance may in part dictate differing susceptibility to respiratory viral infections.
    DOI:  https://doi.org/10.1371/journal.ppat.1012449
  42. Clin Microbiol Rev. 2025 Jan 14. e0009824
    The endothelium at the interface between tissues and Staphylococcus aureus in the bloodstream.
    Pietro Speziale, Timothy J Foster, Carla Renata Arciola.
      SUMMARYStaphylococcus aureus is a major human pathogen. It can cause many types of infections, in particular bacteremia, which frequently leads to infective endocarditis, osteomyelitis, sepsis, and other debilitating diseases. The development of secondary infections is based on the bacterium's ability to associate with endothelial cells lining blood vessels. The success of endothelial colonization and infection by S. aureus relies on its ability to express a wide array of cell wall-anchored and secreted virulence factors. Establishment of endothelial infection by the pathogen is a multistep process involving adhesion, invasion, extravasation, and dissemination of the bacterium into surrounding tissues. The process is dependent on the type of endothelium in different organs (tissues) and pathogenetic potential of the individual strains. In this review, we report an update on the organization of the endothelium in the vessels, the structure and function of the virulence factors of S. aureus, and the several aspects of bacteria-endothelial cell interactions. After these sections, we will discuss recent advances in understanding the specific mechanisms of infections that develop in the heart, bone and joints, lung, and brain. Finally, we describe how neutrophils bind to endothelial cells, migrate to the site of infection to kill bacteria in the tissues, and how staphylococci counteract neutrophils' actions. Knowledge of the molecular details of S. aureus-endothelial cell interactions will promote the development of new therapeutic strategies and tools to combat this formidable pathogen.
    Keywords:  Staphylococcus aureus; adhesion; dissemination; endothelium; inflammation; invasion; neutrophil transmigration; organ-specific infection; virulence factor
    DOI:  https://doi.org/10.1128/cmr.00098-24
  43. Biomed Pharmacother. 2025 Jan 14. pii: S0753-3322(25)00050-2. [Epub ahead of print]183 117856
    SMEPPI: An indenone derivative that selectively inhibits M1 macrophage activation and enhances phagocytic activity.
    Ji Hyun Oh, Mi Gyeong Jeong, Soheun Lee, Jihae Lim, Jio Kang, Myung Ae Bae, Jin-Hee Ahn, Jeong-Ho Hong, Eun Sook Hwang.
      SMEPPI is a small molecule synthesized as a derivative of KR-62980 that has anti-diabetic and anti-inflammatory activities. Despite the established physiological effects of KR-62980, the effects and benefits of SMEPPI remain largely unexplored. This study investigated the immunomodulatory functions of SMEPPI on macrophages and inflammatory diseases. SMEPPI did not affect the differentiation and maturation of bone marrow-derived monocytes into macrophages, nor did it affect the proliferation of M1 or M2 macrophages. Although SMEPPI did not affect M2 macrophage polarization, it significantly inhibited IL-1β and IL-6 cytokine production in both M1 macrophages and activated RAW264.7 macrophages. Importantly, SMEPPI inhibited the expression and phosphorylation of NF-κB p65 through inhibition of Akt expression, preventing its translocation to the nucleus. It also promoted p65 degradation through the stimulation of the proteasomal degradation pathway by inducing the expression of proteasome-related genes, thereby inhibiting p65 transcriptional activity. SMEPPI also enhanced the expression of various molecules associated with macrophage phagocytosis, including CD68, CD33, and lectins, thereby increasing phagocytic activity. Moreover, SMEPPI mitigated lipopolysaccharides-induced acute lung injury by suppressing IL-1β and IL-6 production in M1 macrophages and reduced mortality related to severe lung injury. These findings indicate that SMEPPI effectively regulates inflammatory diseases by impeding p65-induced cytokine production and enhancement of phagocytosis by M1 macrophages.
    Keywords:  Acute lung injury; Macrophage; Mortality; P65; Phagocytosis; SMEPPI
    DOI:  https://doi.org/10.1016/j.biopha.2025.117856
  44. Signal Transduct Target Ther. 2025 Jan 17. 10(1): 12
    Tissue-resident immune cells: from defining characteristics to roles in diseases.
    Jia Li, Chu Xiao, Chunxiang Li, Jie He.
      Tissue-resident immune cells (TRICs) are a highly heterogeneous and plastic subpopulation of immune cells that reside in lymphoid or peripheral tissues without recirculation. These cells are endowed with notably distinct capabilities, setting them apart from their circulating leukocyte counterparts. Many studies demonstrate their complex roles in both health and disease, involving the regulation of homeostasis, protection, and destruction. The advancement of tissue-resolution technologies, such as single-cell sequencing and spatiotemporal omics, provides deeper insights into the cell morphology, characteristic markers, and dynamic transcriptional profiles of TRICs. Currently, the reported TRIC population includes tissue-resident T cells, tissue-resident memory B (BRM) cells, tissue-resident innate lymphocytes, tissue-resident macrophages, tissue-resident neutrophils (TRNs), and tissue-resident mast cells, but unignorably the existence of TRNs is controversial. Previous studies focus on one of them in specific tissues or diseases, however, the origins, developmental trajectories, and intercellular cross-talks of every TRIC type are not fully summarized. In addition, a systemic overview of TRICs in disease progression and the development of parallel therapeutic strategies is lacking. Here, we describe the development and function characteristics of all TRIC types and their major roles in health and diseases. We shed light on how to harness TRICs to offer new therapeutic targets and present burning questions in this field.
    DOI:  https://doi.org/10.1038/s41392-024-02050-5
  45. EMBO J. 2025 Jan 15.
    A novel human fetal lung-derived alveolar organoid model reveals mechanisms of surfactant protein C maturation relevant to interstitial lung disease.
    Kyungtae Lim, Eimear N Rutherford, Livia Delpiano, Peng He, Weimin Lin, Dawei Sun, Dick J H Van den Boomen, James R Edgar, Jae Hak Bang, Alexander Predeus, Sarah A Teichmann, John C Marioni, Lydia E Matesic, Joo-Hyeon Lee, Paul J Lehner, Stefan J Marciniak, Emma L Rawlins, Jennifer A Dickens.
      Alveolar type 2 (AT2) cells maintain lung health by acting as stem cells and producing pulmonary surfactant. AT2 dysfunction underlies many lung diseases, including interstitial lung disease (ILD), in which some inherited forms result from the mislocalization of surfactant protein C (SFTPC) variants. Lung disease modeling and dissection of the underlying mechanisms remain challenging due to complexities in deriving and maintaining human AT2 cells ex vivo. Here, we describe the development of mature, expandable AT2 organoids derived from human fetal lungs which are phenotypically stable, can differentiate into AT1-like cells, and are genetically manipulable. We use these organoids to test key effectors of SFTPC maturation identified in a forward genetic screen including the E3 ligase ITCH, demonstrating that their depletion phenocopies the pathological SFTPC redistribution seen for the SFTPC-I73T variant. In summary, we demonstrate the development of a novel alveolar organoid model and use it to identify effectors of SFTPC maturation necessary for AT2 health.
    Keywords:  E3 Ligase; ITCH; Pulmonary Fibrosis; Stem Cell; Surfactant Protein C
    DOI:  https://doi.org/10.1038/s44318-024-00328-6
  46. Leukemia. 2025 Jan 15.
    Multi-omic analysis of chronic myelomonocytic leukemia monocytes reveals metabolic and immune dysregulation leading to altered macrophage polarization.
    Hasse M Addinsell, Rachel Cant, Nathan J Hull, Yu-Hung Wang, Tim C P Somervaille, Daniel H Wiseman, Kiran Batta.
      
    DOI:  https://doi.org/10.1038/s41375-024-02511-4
  47. Cell Metab. 2025 Jan 10. pii: S1550-4131(24)00482-0. [Epub ahead of print]
    Nuclear adenine activates hnRNPA2B1 to enhance antibacterial innate immunity.
    Shihao Zhang, Zenghui Cui, Danni Zhang, Deyu Zhang, Ke Jin, Zemeng Li, Bo Li, Boyi Cong, Juan Liu, Lei Wang, Mingyue Wen, Xuetao Cao.
      Bacterial infection reprograms cellular metabolism and epigenetic status, but how the metabolic-epigenetic crosstalk empowers host antibacterial defense remains unclear. Here, we report that heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is a sensor for metabolite adenine to launch an antimicrobial innate response through increasing Il1b transcription. Myeloid cell-specific Hnrnpa2b1-cKO mice are more susceptible to bacterial infection, while interleukin 1 beta (IL-1β) supplementation rescues the phenotype. Through a large-scale metabolites-hnRNPA2B1 interaction screen, we reveal that adenine directly binds and activates hnRNPA2B1 to mediate innate antibacterial response. Mechanistically, adenine directly recruits hnRNPA2B1 to Il1b enhancers, and hnRNPA2B1 increases Il1b enhancer chromatin accessibility through binding and recruiting nucleolin and fat mass and obesity-associated protein (FTO) to mediate Il1b enhancer DNA N6-methyladenosine (6mA) demethylation. Furthermore, bacterial infection elevates nuclear adenine at the early stage of infection, and in vivo adenine administration protects mice from death upon bacterial infection through the hnRNPA2B1-IL-1β circuit. Our findings offer new insights into metabolic-epigenetic crosstalk relevant to antibacterial innate immunity and indicate potential approaches for treating bacterial infections.
    Keywords:  DNA N(6)-methyladenosine; adenine; antibacterial immunity; hnRNPA2B1; interleukin 1; nucleolin
    DOI:  https://doi.org/10.1016/j.cmet.2024.11.014
  48. MedComm (2020). 2025 Feb;6(2): e70049
    H3K14la drives endothelial dysfunction in sepsis-induced ARDS by promoting SLC40A1/transferrin-mediated ferroptosis.
    Fangchen Gong, Xiangtao Zheng, Wen Xu, Rongli Xie, Wenbin Liu, Lei Pei, Ming Zhong, Wen Shi, Hongping Qu, Enqiang Mao, Zhitao Yang, Ranran Li, Erzhen Chen, Ying Chen.
      Pulmonary endothelial cell (EC) activation is a key factor in acute respiratory distress syndrome (ARDS). In sepsis, increased glycolysis leads to lactate buildup, which induces lysine lactylation (Kla) on histones and other proteins. However, the role of protein lactylation in EC dysfunction during sepsis-induced ARDS remains unclear. Integrative lactylome and proteome analyses were performed to identify the global lactylome profile in the lung tissues of septic mice. Cut&Tag analysis was used to identify the transcriptional targets of histone H3 lysine 14 lactylation (H3K14la) in ECs. Septic mice presented elevated levels of lactate and H3K14la in lung tissues, particularly in pulmonary ECs. Suppressing glycolysis reduced both H3K14la and EC activation, suggesting a link between glycolysis and lactylation. Moreover, H3K14la was enriched at promoter regions of ferroptosis-related genes such as transferrin receptor (TFRC) and solute carrier family 40 member 1 (SLC40A1), which contributed to EC activation and lung injury under septic conditions. For the first time, we reported the role of lactate-dependent H3K14 lactylation in regulating EC ferroptosis to promote vascular dysfunction during sepsis-induced lung injury. Our findings suggest that manipulation of the glycolysis/H3K14la/ferroptosis axis may provide novel therapeutic approaches for sepsis-associated ARDS.
    Keywords:  endothelial dysfunction; ferroptosis; lactylation; lung injury; sepsis
    DOI:  https://doi.org/10.1002/mco2.70049
  49. Wound Repair Regen. 2025 Jan-Feb;33(1):33(1): e13253
    Bacteria in hypertrophic scars promote scar formation through HSBP1-mediated autophagy.
    Bo Yuan, Jiarong Yu, Jiaoyun Dong, Zhigang Mao, Xiqiao Wang.
      Bacterial colonisation in hypertrophic scars (HSs) has been reported, yet the precise mechanism of their contribution to scar formation remains elusive. To address this, we examined HS and normal skin (NS) tissues through Gram staining and immunofluorescence. We co-cultured fibroblasts with heat-inactivated Staphylococcus aureus (S. aureus) and evaluated their levels of apoptosis and proliferation by flow cytometry and Cell Counting Kit-8 assay, respectively. Additionally, we performed proteomic analysis and western blotting to identify upregulated proteins. To assess autophagy levels, we examined light chain 3 (LC3) expression through western blotting and immunofluorescence, and transmission electron microscopy (TEM) was performed to detect autophagy-associated vesicles. Our results demonstrated a notable increase in bacterial load, primarily S. aureus, in HS tissues. Furthermore, S. aureus promoted fibroblast proliferation and enhanced the expression of profibrotic markers such as transforming growth factor β1 (TGF-β1), vascular endothelial growth factor (VEGF), collagen I, collagen III and α smooth muscle actin (α-SMA). Proteomic analysis highlighted heat shock factor-binding protein 1 (HSBP1) as a key upregulated protein mediating the profibrotic effects induced by S. aureus. Knockdown of HSBP1 reversed these effects. Intriguingly, HSBP1 also upregulated LC3 and Beclin-1 expression and increased the number of autophagosomes in fibroblasts. Finally, when fibroblasts stimulated by S. aureus were treated with HSBP1 siRNA, autophagy levels decreased significantly. Collectively, our findings suggest that S. aureus, via HSBP1, stimulates fibroblast proliferation and promotes their transition into myofibroblasts, triggering autophagy and fibrosis. These results underscore the potential of HSBP1 as a therapeutic target for the management of HSs.
    Keywords:  HSBP1; S. aureus; autophagy; fibroblasts; hypertrophic scar
    DOI:  https://doi.org/10.1111/wrr.13253
  50. Adv Sci (Weinh). 2025 Jan 15. e2406654
    Proximity Labeling and Genetic Screening Reveal that DSG2 is a Counter Receptor of Siglec-9 and Suppresses Macrophage Phagocytosis.
    Ying Wu, Yuyu You, Tingsong Jiang, Yuqi He, Qingchi Fan, Xinlei Zeng, Ting Li, Yuxing Lu, Liang Qi, Fengxia Zhou, Lingyu Sun, Danyang Wang, Yong Zou, Guigen Zhang, Yanqiu Yuan, Yang Mao.
      Cancer cells present sialylated glycoconjugates that modulate the activity of various immune cells within the tumor microenvironment through trans interaction with immunosuppressive Siglec receptors. Identifying counter receptors for Siglecs can provide valuable targets for cancer immunotherapy, but it presents significant challenges. Here, the identification of DSG2 (Desmoglein 2) as a dominant counter receptor of Siglec-9 in melanoma cells is reported, using a workflow that combines the strength of proximity labeling and the advantage of CRISPR knockout screening. It is further demonstrated that the interaction between DSG2 and Siglec-9 is mainly dependent on sialic acid-bearing N-glycans on DSG2. Importantly, blocking trans interaction between DSG2 and Siglec-9 significantly enhances macrophage phagocytosis of melanoma cells and, to a lesser extent, other cancer cells. The work thus suggests sialylated DSG2 as a potential "don't eat me" signal molecule with therapeutic potentials in cancer immunotherapy.
    Keywords:  DSG2; genetic screening; phagocytosis; proximity labeling; siglec‐9
    DOI:  https://doi.org/10.1002/advs.202406654
  51. Immunity. 2025 Jan 14. pii: S1074-7613(24)00571-5. [Epub ahead of print]58(1): 5-7
    Mitochondria and NLRP3: To die or inflame.
    Shuangshuang Yang, Guannan Huang, Jenny P-Y Ting.
      Mitochondria play critical roles in intrinsic apoptosis and NLRP3 inflammasome activation, but how these processes are interconnected remains unclear. In this issue of Immunity, Saller et al. unveiled the complexity of NLRP3 activators, highlighting mitochondria's roles in switching apoptosis to NLRP3 inflammasome activation.
    DOI:  https://doi.org/10.1016/j.immuni.2024.12.007
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