bims-bac4me 2025-01-05 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–01–05
35 papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

Matrix metalloproteinase-12 by M2 macrophages induced epithelial to mesenchymal transition in chronic rhinosinusitis with nasal polyps.
Lactobacilli-host interactions inhibit Staphylococcus aureus and Escherichia coli-induced cell death and invasion in a cellular model of infection.
Innate immune barrier against oncogenic transformation.
Metabolic Reprograming of Macrophages: A New Direction in Traditional Chinese Medicine for Treating Liver Failure.
Significance of host antimicrobial peptides in the pathogenesis and treatment of acne vulgaris.
High-dose intravenous BCG vaccination induces enhanced immune signaling in the airways.
The importance of Fcγ and C-type lectin receptors in host immune responses during Pneumocystis pneumonia.
The Role of Innate Priming in Modifying Tumor-associated Macrophage Phenotype.
Dynamic interplay of autophagy and membrane repair during Mycobacterium tuberculosis Infection.
Profiling endogenous airway proteases and antiproteases and modeling proteolytic activation of Influenza HA using in vitro and ex vivo human airway surface liquid samples.
Lactobacillus crispatus S-layer proteins modulate innate immune response and inflammation in the lower female reproductive tract.
Application of Macrophage Subtype Analysis in Acute Lung Injury/Acute Respiratory Distress Syndrome.
Commensal-pathogen dynamics structure disease outcomes during Clostridioides difficile colonization.
Janus PEGylated CuS-engineered Lactobacillus casei combats biofilm infections via metabolic interference and innate immunomodulation.
Microbial adaptive pathogenicity strategies to the host inflammatory environment.
Transplantation of gasdermin pores by extracellular vesicles propagates pyroptosis to bystander cells.
Rheological comparison of sputum and reconstituted airway epithelium mucus.
A postbiotic exopolysaccharide synergizes with Lactobacillus acidophilus to reduce intestinal inflammation in a mouse model of colitis.
Flavuside B exhibits antioxidant and anti-inflammatory properties in Staphylococcus aureus infected skin wound and affect the expression of genes controlling bacterial quorum sensing.
O-GlcNAcylation dictates pyroptosis.
Metagenomic immunoglobulin sequencing reveals IgA coating of microbial strains in the healthy human gut.
Hidden features: CD36/SR-B2, a master regulator of macrophage phenotype/function through metabolism.
mTOR Signaling Regulates Multiple Metabolic Pathways in Human Lung Fibroblasts After TGF-β and in Pulmonary Fibrosis.
Establishment of nasal and olfactory epithelium organoids for unveiling mechanism of tissue regeneration and pathogenesis of nasal diseases.
Lipids guide T cell antitumor immunity by shaping their metabolic and functional fitness.
CD147 mitochondria translocation induced airway remodeling in asthmatic mouse models by regulating M2 macrophage polarization via ANT1-mediated mitophagy.
Innate immune memory in chronic HIV and HIV-associated neurocognitive disorders (HAND): potential mechanisms and clinical implications.
Revisiting surfactant protein D: an immune surveillance molecule bridging innate and adaptive immunity.
Functional diversity of cardiac macrophages in health and disease.
Trained innate immunity as a potential link between preeclampsia and future cardiovascular disease.
In defence of ferroptosis.
Innate immune cells link dietary cues to normal and abnormal metabolic regulation.
A thermodynamic bottleneck in the TCA cycle contributes to acetate overflow in Staphylococcus aureus.
Cytokine-armed pyroptosis induces antitumor immunity against diverse types of tumors.
Metformin improves Mycobacterium avium infection by strengthening macrophage antimicrobial functions.

PLoS One. 2024 ;19(12): e0313097

Matrix metalloproteinase-12 by M2 macrophages induced epithelial to mesenchymal transition in chronic rhinosinusitis with nasal polyps.

Joo-Hoo Park, Jae-Min Shin, Hyun-Woo Yang, Tae Hoon Kim, Seung Hoon Lee, Ok Sarah Shin, Il-Ho Park.

Th2 inflammation and epithelial-mesenchymal transition (EMT) play crucial roles in the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP). This study aimed to investigate the hypothesis that MMP-12, produced by M2 macrophages, induces EMT in nasal epithelial cells, thereby contributing to airway inflammation and remodeling in CRSwNP. The expression levels of MMP-12 were measured by RT-PCR in CRS nasal mucosa and THP-1 cells. mRNA and protein levels of E-cadherin, vimentin, α-SMA, and fibronectin were determined using RT-PCR, western blotting, and immunofluorescence staining in primary nasal epithelial cells and air-liquid interface culture. The expression of MMP-12 was significantly increased in CRSwNP and M2-like THP-1 cells. In co-culture with primary nasal epithelial cells and M2-like THP-1 cells, E-cadherin expression was inhibited, and fibronectin, vimentin, and α-SMA expression were increased. MMP-12 decreased E-cadherin but induced fibronectin, vimentin, and α-SMA mRNA and protein expression in primary nasal epithelial cells and air-liquid interface culture. MMP408, an MMP-12 inhibitor, inhibited EMT-related factors. These findings suggest that MMP-12 expression in M2 macrophages induces EMT in nasal epithelial cells and may contribute to the pathogenesis of CRSwNP.

DOI: https://doi.org/10.1371/journal.pone.0313097
Front Microbiol. 2024 ;15 1501119

Lactobacilli-host interactions inhibit Staphylococcus aureus and Escherichia coli-induced cell death and invasion in a cellular model of infection.

Despoina Eugenia Kiousi, Maria Panopoulou, Aglaia Pappa, Alex Galanis.



Keywords:  Lactiplantibacillus plantarum; competitive exclusion; dual RNA-seq; pathogen invasion; pathogen-induced cytotoxicity; probiotics; proteomics; transcriptomics

DOI:  https://doi.org/10.3389/fmicb.2024.1501119
Nat Immunol. 2025 Jan;26(1): 13-14

Innate immune barrier against oncogenic transformation.

DOI: https://doi.org/10.1038/s41590-024-02043-0
J Immunol Res. 2024 ;2024 5891381

Metabolic Reprograming of Macrophages: A New Direction in Traditional Chinese Medicine for Treating Liver Failure.

Junli Zhang, Na Li, Xiaoyu Hu.

  Acute liver failure (ALF) is a fulminant clinical syndrome that usually leads to multiple organ failure and high mortality. Macrophages play a crucial role in the initiation, development, and recovery of ALF. Targeting macrophages through immunotherapy holds significant promise as a therapeutic strategy. These cells exhibit remarkable plasticity, enabling them to differentiate into various subtypes based on changes in their surrounding microenvironment. M1-type macrophages are associated with a pro-inflammatory phenotype and primarily rely predominantly on glycolysis. In contrast, M2-type macrophages, which are characterized by anti-inflammatory phenotype, predominantly obtain their energy from oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). Shifting macrophage metabolism from glycolysis to OXPHOS inhibits M1 macrophage activation and promotes M2 macrophage activation, thereby exerting anti-inflammatory and reparative effects. This study elucidates the relationship between macrophage activation and glucose metabolism reprograming from an immunometabolism perspective. A comprehensive literature review revealed that several signaling pathways may regulate macrophage polarization through energy metabolism, including phosphatidyl-inositol 3-kinase/protein kinase B (PI3K/AKT), mammalian target of rapamycin (mTOR)/hypoxia-inducible factor 1α (HIF-1α), nuclear factor-κB (NF-κB), and AMP-activated protein kinase (AMPK), which exhibit crosstalk with one another. Additionally, we systematically reviewed several traditional Chinese medicine (TCM) monomers that can modulate glucose metabolism reprograming and influence the polarization states of M1 and M2 macrophages. This review aimed to provide valuable insights that could contribute to the development of new therapies or drugs for ALF.

Keywords:  Chinese medicine; acute liver failure; glucose metabolism; macrophage polarization; signal transduction

DOI:  https://doi.org/10.1155/jimr/5891381
Front Immunol. 2024 ;15 1502242

Significance of host antimicrobial peptides in the pathogenesis and treatment of acne vulgaris.

Agata Lesiak, Paulina Paprocka, Urszula Wnorowska, Angelika Mańkowska, Grzegorz Król, Katarzyna Głuszek, Ewelina Piktel, Jakub Spałek, Sławomir Okła, Krzysztof Fiedoruk, Bonita Durnaś, Robert Bucki.

  Acne vulgaris (AV) is a chronic inflammatory condition of the pilosebaceous units characterized by multiple immunologic, metabolic, hormonal, genetic, psycho-emotional dysfunctions, and skin microbiota dysbiosis. The latter is manifested by a decreased population (phylotypes, i.e., genetically distinct bacterial subgroups that play different roles in skin health and disease) diversity of the predominant skin bacterial commensal - Cutinbacterium acnes. Like in other dysbiotic disorders, an elevated expression of endogenous antimicrobial peptides (AMPs) is a hallmark of AV. AMPs, such as human β-defensins, cathelicidin LL-37, dermcidin, or RNase-7, due to their antibacterial and immunomodulatory properties, function as the first line of defense and coordinate the host-microbiota interactions. Therefore, AMPs are potential candidates for pharmaceutical prophylaxis or treating this condition. This study outlines the current knowledge regarding the importance of AMPs in AV pathomechanism in light of recent transcriptomic studies. In particular, their role in improving the tight junctions (TJs) skin barrier by activating the fundamental cellular proteins, such as PI3K, GSK-3, aPKC, and Rac1, is discussed. We hypothesized that the increased expression of AMPs and their patterns in AV act as a compensatory mechanism to protect the skin with an impaired permeability barrier. Therefore, AMPs could be key determinants in regulating AV development and progression, linking acne-associated immune responses and metabolic factors, like insulin/IGF-1 and PI3K/Akt/mTOR/FoxO1 signaling pathways or glucotoxicity. Research and development of anti-acne AMPs are also addressed.

Keywords:  Cutibacterium acnes; acne vulgaris; antimicrobial peptides; inflammation; skin dysbiosis

DOI:  https://doi.org/10.3389/fimmu.2024.1502242
Sci Adv. 2025 Jan 03. 11(1): eadq8229

High-dose intravenous BCG vaccination induces enhanced immune signaling in the airways.

Joshua M Peters, Edward B Irvine, Mohau S Makatsa, Jacob M Rosenberg, Marc H Wadsworth, Travis K Hughes, Matthew S Sutton, Sarah K Nyquist, Joshua D Bromley, Rajib Mondal, Mario Roederer, Robert A Seder, Patricia A Darrah, Galit Alter, Chetan Seshadri, JoAnne L Flynn, Alex K Shalek, Sarah M Fortune, Bryan D Bryson.

Intradermal Bacillus Calmette-Guérin (BCG) is the most widely administered vaccine, but it does not sufficiently protect adults against pulmonary tuberculosis. Recent studies in nonhuman primates show that intravenous BCG administration offers superior protection against Mycobacterium tuberculosis (Mtb). We used single-cell analysis of bronchoalveolar lavage cells from rhesus macaques vaccinated via different routes and doses of BCG to identify alterations in the immune ecosystem in the airway following vaccination. Our findings reveal that high-dose intravenous BCG induces an influx of polyfunctional T cells and macrophages in the airways, with alveolar macrophages from high-dose intravenous BCG displaying a basal activation state in the absence of purified protein derivative stimulation, defined in part by interferon signaling. Enhanced intercellular immune signaling and stronger T helper 1-T helper 17 transcriptional responses were observed following purified protein derivative stimulation. These results suggest that high-dose intravenous BCG vaccination creates a specialized immune environment that primes airway cells for effective Mtb clearance.

DOI: https://doi.org/10.1126/sciadv.adq8229
Infect Immun. 2024 Dec 31. e0027624

The importance of Fcγ and C-type lectin receptors in host immune responses during Pneumocystis pneumonia.

Theodore J Kottom, Eva M Carmona, Kyle Schaefbauer, Kimberly E Stelzig, Madeline R Pellegrino, Marc Bindzus, Andrew H Limper.

  Pneumocystis jirovecii pneumonia (PJP) remains a significant cause of morbidity and mortality during AIDS. In AIDS, the absence of CD4 immunity results in exuberant and often fatal PJP. In addition, organism clearance requires a balanced macrophage response since excessive inflammation promotes lung injury and respiratory failure. Corticosteroids given in addition to antibiotics significantly improve outcomes during PJP. However, concerns exist that corticosteroids further suppress immunity and increase co-infections. New strategies to promote killing and clearance of Pneumocystis while balancing lung inflammation are required. Prior studies have shown that innate immunity to Pneumocystis is mediated by C-type lectin receptors (CLRs) on macrophages and involves downstream CARD9 activation. CARD9 can be targeted by a novel specific small molecule inhibitor (BRD5529) that significantly reduces inflammatory signaling by macrophages. CARD9 serves as the central intracellular molecule through which Dectin-1, Dectin-2, Mincle, and other CLRs signal. Dectin-1 CLR is activated through its own intracytoplasmic domain, whereas other innate CLRs (e.g., Dectin-2 and Mincle) require interactions with a common Fc-gamma receptor (FcγR) accessory chain to mediate responses. We now observe that mice double deficient in both Dectin-1 and Fcer1g (which lack the FcγR gamma chain) exhibit markedly reduced organism clearance compared with Card9-/- infected animals. These mice also possess deficiencies in immunoglobulin (Ig) Fc receptors directly mediating antibody responses, further implicating altered humoral responses in Pneumocystis killing. We further demonstrate in the Pneumocystis pneumonia (PCP) mouse model that BRD5529 administration successfully suppresses inflammatory cytokines. Our data support that innate immune responses through the CLR-CARD9 axis and humoral response act together to mediate effective responses resulting in optimal organism killing and generation of host inflammatory responses. Furthermore, host lung inflammation during PCP may be successfully reduced with a novel CARD9 small molecule inhibitor.IMPORTANCEPneumocystis pneumonia (PCP) causes severe respiratory impairment in hosts with suppressed immunity, particularly those with CD4 deficiencies, such as HIV. In addition to lymphocytic immunity, both innate and humoral immunities also participate in host defense against Pneumocystis. In the current studies, we defined the relative roles of CLR receptor-mediated inflammation, as well as FcgR-related inflammation and clearance of Pneumocystis organisms. Our studies reveal important roles for CLR activities for inducing lung inflammation, which can be ameliorated with a novel small molecule inhibitor of the CARD9 adaptor protein that is necessary for CLR signaling. In contrast, FcgR has a dominant role in organism clearance, underscoring an integral role of humoral responses for the elimination of this infection.

Keywords:  C-lectin receptor; Fc receptors; Pneumocystis carinii; clearance; inflammation

DOI:  https://doi.org/10.1128/iai.00276-24
Front Biosci (Landmark Ed). 2024 Dec 17. 29(12): 418

The Role of Innate Priming in Modifying Tumor-associated Macrophage Phenotype.

Ben Topham, Barry Hock, Elisabeth Phillips, George Wiggins, Margaret Currie.

  Tumor-associated macrophages (TAMs) are innate immune cells that exert far reaching influence over the tumor microenvironment (TME). Depending on cues within the local environment, TAMs may promote tumor angiogenesis, cancer cell invasion and immunosuppression, or, alternatively, inhibit tumor progression via neoantigen presentation, tumoricidal reactive oxygen species generation and pro-inflammatory cytokine secretion. Therefore, TAMs have a pivotal role in determining tumor progression and response to therapy. TAM phenotypes are driven by cytokines and physical cues produced by tumor cells, adipocytes, fibroblasts, pericytes, immune cells, and other cells within the TME. Research has shown that TAMs can be primed by environmental stimuli, adding another layer of complexity to the environmental context that determines TAM phenotype. Innate priming is a functional consequence of metabolic and epigenetic reprogramming of innate cells by a primary stimulant, resulting in altered cellular response to future secondary stimulation. Innate priming offers a novel target for development of cancer immunotherapy and improved prognosis of disease, but also raises the risk of exacerbating existing inflammatory pathologies. This review will discuss the mechanisms underlying innate priming including metabolic and epigenetic modification, its relevance to TAMs and tumor progression, and possible clinical implications for cancer treatment.

Keywords:  cancer; epigenetic modification; innate priming; metabolic modification; tumor-associated macrophage (TAM)

DOI:  https://doi.org/10.31083/j.fbl2912418
PLoS Pathog. 2025 Jan 02. 21(1): e1012830

Dynamic interplay of autophagy and membrane repair during Mycobacterium tuberculosis Infection.

Jacques Augenstreich, Anna T Phan, Charles N S Allen, Anushka Poddar, Hanzhang Chen, Lalitha Srinivasan, Volker Briken.

Autophagy plays a crucial role in the host response to Mycobacterium tuberculosis (Mtb) infection, yet the dynamics and regulation of autophagy induction on Mtb-containing vacuoles (MCVs) remain only partially understood. We employed time-lapse confocal microscopy to investigate the recruitment of LC3B (LC3), a key autophagy marker, to MCVs at the single cell level with our newly developed workflow for single cell and single MCV tracking and fluorescence quantification. We show that approximately 70% of MCVs exhibited LC3 recruitment but that was lost in about 40% of those MCVs. The LC3 recruitment to MCVs displayed a high variability in timing that was independent of the size of the MCV or the bacterial burden. Most notably, the LC3-positive MCVs did not acidify, indicating that LC3 recruitment does not necessarily lead to the formation of mature autophagolysosomes. Interferon-gamma pre-treatment did not affect LC3 recruitment frequency or autophagosome acidification but increased the susceptibility of the macrophage to Mtb-induced cell death. LC3 recruitment and lysotracker staining were mutually exclusive events, alternating on some MCVs multiple times thus demonstrating a reversible aspect of the autophagy response. The LC3 recruitment was associated with galectin-3 and oxysterol-binding protein 1 staining, indicating a correlation with membrane damage and repair mechanisms. ATG7 knock-down did not impact membrane repair, suggesting that autophagy is not directly involved in this process but is coregulated by the membrane damage of MCVs. In summary, our findings provide novel insights into the dynamic and variable nature of LC3 recruitment to the MCVs over time during Mtb infection. Our data does not support a role for autophagy in either cell-autonomous defense against Mtb or membrane repair of the MCV in human macrophages. In addition, the combined dynamics of LC3 recruitment and Lysoview staining emerged as promising markers for investigating the damage and repair processes of phagosomal membranes.

DOI: https://doi.org/10.1371/journal.ppat.1012830
PLoS One. 2024 ;19(12): e0306197

Profiling endogenous airway proteases and antiproteases and modeling proteolytic activation of Influenza HA using in vitro and ex vivo human airway surface liquid samples.

Stephanie A Brocke, Boris Reidel, Camille Ehre, Meghan E Rebuli, Carole Robinette, Kevin D Schichlein, Christian A Brooks, Ilona Jaspers.

Imbalance of airway proteases and antiproteases has been implicated in diseases such as COPD and environmental exposures including cigarette smoke and ozone. To initiate infection, endogenous proteases are commandeered by respiratory viruses upon encountering the airway epithelium. The airway proteolytic environment likely contains redundant antiproteases and proteases with diverse catalytic mechanisms, however a proteomic profile of these enzymes and inhibitors in airway samples has not been reported. The objective of this study was to first profile extracellular proteases and antiproteases using human airway epithelial cell cultures and ex vivo nasal epithelial lining fluid (NELF) samples. Secondly, we present an optimized method for probing the proteolytic environment of airway surface liquid samples (in vitro and ex vivo) using fluorogenic peptides modeling the cleavage sites of respiratory viruses. We detected 48 proteases in the apical wash of cultured human nasal epithelial cells (HNECs) (n = 6) and 57 in NELF (n = 13) samples from healthy human subjects using mass-spectrometry based proteomics. Additionally, we detected 29 and 48 antiproteases in the HNEC apical washes and NELF, respectively. We observed large interindividual variability in rate of cleavage of an Influenza H1 peptide in the ex vivo clinical samples. Since protease and antiprotease levels have been found to be altered in the airways of smokers, we compared proteolytic cleavage in ex vivo nasal lavage samples from male/female smokers and non-smokers. There was a statistically significant increase in proteolysis of Influenza H1 in NLF from male smokers compared to female smokers. Furthermore, we measured cleavage of the S1/S2 site of SARS-CoV, SARS-CoV-2, and SARS-CoV-2 Delta peptides in various airway samples, suggesting the method could be used for other viruses of public health relevance. This assay presents a direct and efficient method of evaluating the proteolytic environment of human airway samples in assessment of therapeutic treatment, exposure, or underlying disease.

DOI: https://doi.org/10.1371/journal.pone.0306197
Nat Commun. 2024 Dec 30. 15(1): 10879

Lactobacillus crispatus S-layer proteins modulate innate immune response and inflammation in the lower female reproductive tract.

Alexiane Decout, Ioannis Krasias, Lauren Roberts, Belen Gimeno Molina, Chloé Charenton, Daniel Brown Romero, Qiong Y Tee, Julian R Marchesi, Sherrianne Ng, Lynne Sykes, Phillip R Bennett, David A MacIntyre.

Lactobacillus species dominance of the vaginal microbiome is a hallmark of vaginal health. Pathogen displacement of vaginal lactobacilli drives innate immune activation and mucosal barrier disruption, increasing the risks of STI acquisition and, in pregnancy, of preterm birth. We describe differential TLR mediated activation of the proinflammatory transcription factor NF-κB by vaginal pathogens and commensals. Vaginal Lactobacillus strains associated with optimal health selectively interact with anti-inflammatory innate immune receptors whereas species associated with suboptimal health including L. iners and Gardnerella vaginalis interact with both pro- and anti-inflammatory receptors. Anti-inflammatory action of L. crispatus is regulated by surface layer protein (SLPs)-mediated shielding of TLR ligands and selective interaction with the anti-inflammatory receptor DC-SIGN. Detection of SLPs within cervicovaginal fluid samples is associated with decreased concentrations of pro-inflammatory cytokines in Lactobacillus crispatus-dominated samples. These data offer mechanistic insights into how vaginal microbiota modulate host immune response and thus reproductive health and disease states.

DOI: https://doi.org/10.1038/s41467-024-55233-7
Front Biosci (Landmark Ed). 2024 Dec 06. 29(12): 412

Application of Macrophage Subtype Analysis in Acute Lung Injury/Acute Respiratory Distress Syndrome.

Jiajia Tang, Jun Shi, Zhihai Han, Xuxin Chen.

  Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common critical illness. Supportive therapy is still the main strategy for ALI/ARDS. Macrophages are the predominant immune cells in the lungs and play a pivotal role in maintaining homeostasis, regulating metabolism, and facilitating tissue repair. During ALI/ARDS, these versatile cells undergo polarization into distinct subtypes with significant variations in transcriptional profiles, developmental trajectory, phenotype, and functionality. This review discusses developments in the analysis of alveolar macrophage subtypes in the study of ALI/ARDS, and the potential value of targeting new macrophage subtypes in the diagnosis, prognostic evaluation, and treatment of ALI/ARDS.

Keywords:  ALI (acute lung injury); ARDS (acute respiratory distress); macrophage polarization; subtype analysis

DOI:  https://doi.org/10.31083/j.fbl2912412
Cell Host Microbe. 2024 Dec 18. pii: S1931-3128(24)00447-5. [Epub ahead of print]

Commensal-pathogen dynamics structure disease outcomes during Clostridioides difficile colonization.

Skye R S Fishbein, Anna L DeVeaux, Sakshi Khanna, Aura L Ferreiro, James Liao, Wesley Agee, Jie Ning, Bejan Mahmud, Miranda J Wallace, Tiffany Hink, Kimberly A Reske, Candice Cass, Janaki Guruge, Sidh Leekha, Sunaina Rengarajan, Erik R Dubberke, Gautam Dantas.

  Gastrointestinal colonization by Clostridioides difficile is common in healthcare settings and ranges in presentation from asymptomatic carriage to lethal C. difficile infection (CDI). We used a systems biology approach to investigate why patients colonized with C. difficile have a range of clinical outcomes. Microbiota humanization of germ-free mice with fecal samples from toxigenic C. difficile carriers revealed a spectrum of virulence among clinically prevalent clade 1 lineages and identified candidate taxa, including Blautia, as markers of stable colonization. Using gnotobiotic mice engrafted with defined human microbiota, we validated strain-specific CDI severity across clade 1 strains isolated from patients. Mice engrafted with a community broadly representative of colonized patients were protected from severe disease across all strains without suppression of C. difficile colonization. These results underline the capacity of gut community structure to attenuate a diversity of pathogenic strains without inhibiting colonization, providing insight into determinants of stable C. difficile carriage.

Keywords:  Clostridioides difficile; gastrointestinal infection; gut microbiome

DOI:  https://doi.org/10.1016/j.chom.2024.12.002
Biomaterials. 2024 Dec 26. pii: S0142-9612(24)00596-9. [Epub ahead of print]317 123060

Janus PEGylated CuS-engineered Lactobacillus casei combats biofilm infections via metabolic interference and innate immunomodulation.

Lingtong Kong, Xianli Hu, Demeng Xia, Jianghong Wu, Yangpeng Zhao, Hua Guo, Song Zhang, Chun Qin, Yanjun Wang, Lei Li, Zheng Su, Chen Zhu, Shuogui Xu.

  Bacterial implant-associated infections predominantly contribute to the failure of prosthesis implantation. The local biofilm microenvironment (BME), characterized by its hyperacidic condition and high hydrogen peroxide (H2O2) level, inhibits the host's immune response, thereby facilitating recurrent infections. Here, a Janus PEGylated CuS nanoparticle (CuPen) armed engineered Lactobacillus casei (L. casei) denoted as LC@CuPen, is proposed to interfere with bacterial metabolism and arouse macrophage antibiofilm function. Once LC@CuPen reached the BME, NIR irradiation-activated mild heat damages L. casei and biofilm structure. Meanwhile, the BME-responsive LC@CuPen can catalyze local H2O2 to produce toxic •OH, whereas in normal tissues, the effect of •OH production is greatly reduced due to the higher pH and lower H2O2 concentration. The released bacteriocin from damaged L. casei can destroy the bacterial membrane to enhance the penetration of •OH into damaged biofilm. Excessive •OH interferes with normal bacterial metabolism, resulting in reduced resistance of bacteria to heat stress. Finally, under the action of mild heat treatment, the bacterial biofilm lysed and died. Furthermore, the pathogen-associated molecular patterns (PAMPs) in LC@CuPen can induce M1 polarization of macrophages through NF-κB pathway and promote the release of inflammatory factors. Inflammatory factors enhance the migration of macrophages to the site of infection and phagocytose bacteria, thereby inhibiting the recurrence of infection. Generally, this engineered L. casei program presents a novel perspective for the treatment of bacterial implant-associated infections and serves as a valuable reference for future clinical applications of engineered probiotics.

Keywords:  Bacterial biofilm infection; Bacteriocin; Engineered probiotics; Innate immunomodulation; Macrophage

DOI:  https://doi.org/10.1016/j.biomaterials.2024.123060
FEMS Microbiol Rev. 2024 Dec 28. pii: fuae032. [Epub ahead of print]

Microbial adaptive pathogenicity strategies to the host inflammatory environment.

Sophia U J Hitzler, Candela Fernández, Dolly E Montaño, Axel Dietschmann, Mark S Gresnigt.

  Pathogenic microorganisms can infect a variety of niches in the human body. During infection, microbes can only persist if they adapt adequately to the dynamic host environment and the stresses imposed by the immune system. While viruses entirely rely on host cells to replicate, bacteria and fungi use their pathogenicity mechanisms for the acquisition of essential nutrients that lie under host restriction. An inappropriate deployment of pathogenicity mechanisms will alert host defence mechanisms that aim to eradicate the pathogen. Thus, these adaptations require tight regulation to guarantee nutritional access without eliciting strong immune activation. To work efficiently, the immune system relies on a complex signalling network, involving a myriad of immune mediators, some of which are quite directly associated with imminent danger for the pathogen. To manipulate the host immune system, viruses have evolved cytokine receptors and viral cytokines. However, among bacteria and fungi, selected pathogens have evolved the capacity to use these inflammatory response-specific signals to regulate their pathogenicity. In this review, we explore how bacterial and fungal pathogens can sense the immune system and, use adaptive pathogenicity strategies to evade and escape host defence to ensure their persistence in the host.

Keywords:  adaptation; adaptive prediction; immune escape; immune evasion; immune sensing

DOI:  https://doi.org/10.1093/femsre/fuae032
Cell. 2024 Dec 26. pii: S0092-8674(24)01334-5. [Epub ahead of print]

Transplantation of gasdermin pores by extracellular vesicles propagates pyroptosis to bystander cells.

Skylar S Wright, Puja Kumari, Víctor Fraile-Ágreda, Chengliang Wang, Sonia Shivcharan, Shirin Kappelhoff, Eleonora G Margheritis, Alyssa Matz, Swathy O Vasudevan, Ignacio Rubio, Michael Bauer, Beiyan Zhou, Sivapriya Kailasan Vanaja, Katia Cosentino, Jianbin Ruan, Vijay A Rathinam.

  Pyroptosis mediated by gasdermins (GSDMs) plays crucial roles in infection and inflammation. Pyroptosis triggers the release of inflammatory molecules, including damage-associated molecular patterns (DAMPs). However, the consequences of pyroptosis-especially beyond interleukin (IL)-1 cytokines and DAMPs-that govern inflammation are poorly defined. Here, we show intercellular propagation of pyroptosis from dying cells to bystander cells in vitro and in vivo. We identified extracellular vesicles (EVs) released by pyroptotic cells as the propagator of lytic death to naive cells, promoting inflammation. DNA-PAINT super-resolution and immunoelectron microscopy revealed GSDMD pore structures on EVs released by pyroptotic cells. Importantly, pyroptotic EVs transplant GSDMD pores on the plasma membrane of bystander cells and kill them. Overall, we demonstrate that cell-to-cell vesicular transplantation of GSDMD pores disseminates pyroptosis, revealing a domino-like effect governing disease-associated bystander cell death.

Keywords:  GSDMD; bystander; caspase-1; caspase-11; gasdermin; inflammasomes; pyroptosis; sepsis

DOI:  https://doi.org/10.1016/j.cell.2024.11.018
Sci Rep. 2024 Dec 30. 14(1): 31660

Rheological comparison of sputum and reconstituted airway epithelium mucus.

Lydia Esteban Enjuto, Vassylia Taty Poaty, Mendy Bouveret, Huang Song, Samuel Constant, Jérémy Patarin.

Pulmonary mucus serves as a crucial protective barrier in the respiratory tract, defending against pathogens and contributing to effective clearance mechanisms. In Muco Obstructive Pulmonary Diseases (MOPD), abnormal rheological properties lead to highly viscous mucus, fostering chronic infections and exacerbations. While prior research has linked mucus viscoelasticity to its mucin content, the variability in MOPD patients implies the involvement of other factors. To isolate these effects, mucus produced by epithelia reconstituted in vitro serves as a powerful versatile model for mucin research. This study characterises the rheology of mucus collected from Air-Liquid Interface (ALI) cultures and compares it to sputum samples from MOPD patients, demonstrating that macrorheology with cone-plate geometries is a reproducible method for analysing small mucus quantities from ALI cultures. While sputum samples exhibit similarities in rigidity with ALI mucus, they also display structural differences and variations in their response to substantial deformations. The study highlights the importance of understanding mucus behaviour under large deformations, emphasising the role of ALI cultures as a controlled environment for conducting detailed studies.

DOI: https://doi.org/10.1038/s41598-024-80932-y
Int J Biol Macromol. 2024 Dec 26. pii: S0141-8130(24)09742-3. [Epub ahead of print] 138931

A postbiotic exopolysaccharide synergizes with Lactobacillus acidophilus to reduce intestinal inflammation in a mouse model of colitis.

Chong Ma, Xiaobin Zheng, Qian Zhang, Stephen James Renaud, Hansheng Yu, Yaning Xu, Yuchun Chen, Jing Gong, Yonghua Cai, Yanjun Hong, Hao Li, Qiongfeng Liao, Ying Guo, Liang Kang, Zhiyong Xie.

  Ulcerative colitis (UC) is an inflammatory bowel disease marked by gut inflammation and microbial dysbiosis. Exopolysaccharides (EPS) from probiotic bacteria have been shown to regulate microbial composition and metabolism, but their role in promoting probiotic growth and alleviating inflammation in UC remains unclear. Here, we investigate BLEPS-1, a novel EPS derived from Bifidobacterium longum subsp. longum XZ01, for its ability to promote the growth of Lactobacillus strains. We then tested a synbiotic formulation of BLEPS-1 and L. acidophilus in a DSS-induced UC mouse model. The combination of BLEPS-1 and L. acidophilus alleviated DSS-induced intestinal inflammation, outperforming either component alone. Administration of BLEPS-1 decreased the proportion of M1 macrophages in the intestine, while M2 macrophages were more abundant following L. acidophilus treatment. Together, BLEPS-1 and L. acidophilus synergistically modulated macrophage polarization toward the M2-type. Administration of BLEPS-1 and L. acidophilus together modulated gut microbiota composition and altered the gut metabolic profile, with BLEPS-1 and L. acidophilus promoting metabolism of short-chain fatty acids and aromatic amino acids, respectively. Our study identified a novel synbiotic formulation with potent immunomodulatory and metabolic activity, laying the groundwork for a promising therapeutic strategy to treat intestinal inflammatory diseases such as colitis.

Keywords:  Aromatic amino acid metabolites; Colitis; Exopolysaccharides; Macrophage polarization; Postbiotic; Synbiotic

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.138931
J Appl Microbiol. 2025 Jan 02. pii: lxae318. [Epub ahead of print]

Flavuside B exhibits antioxidant and anti-inflammatory properties in Staphylococcus aureus infected skin wound and affect the expression of genes controlling bacterial quorum sensing.

Ekaterina A Chingizova, Ekaterina A Yurchenko, Sofya S Starnovskaya, Artur R Chingizov, Aleksandra S Kuzmich, Evgeny A Pislyagin, Alexey S Vasilchenko, Darya V Poshvina, Gregory A Shilovsky, Daria V Dibrova, Dmitry L Aminin, Anton N Yurchenko.

   AIMS: The aim of this study was to evaluate the antioxidant and anti-inflammatory effects of marine fungal cerebroside flavuside B (FlaB) on Staphylococcus aureus-infected keratinocytes in in vitro skin wounds and to identify FlaB targets in bacterial and human cells.
METHODS AND RESULTS: A combination of ELISA, plate spectrofluorimetry, and flow cytometry with fluorescence dye staining, scratch assay, and real-time cell imaging techniques was used to investigate the effects of FlaB on S. aureus-infected HaCaT keratinocytes. FlaB decreased ROS levels, NO levels, and TNF-α and IL-18 release in S. aureus-infected HaCaT cells. FlaB reversed the inhibition of HaCaT cell proliferation caused by S. aureus infection. FlaB significantly increased keratinocyte migration and wound healing in an in vitro S. aureus-infected wound skin model. Using real-time qPCR, we found that FlaB caused a 1.7-fold reduction in agrA expression, which controls quorum sensing system in S. aureus. Bioinformatics analysis and molecular docking, together with experimental data, suggest that FlaB targets the pro/antioxidant defense system in human cells.
CONCLUSIONS: Thus, FlaB can play a dual role as an antibacterial and pro/antioxidant machinery modulator, providing an observable positive effect in S. aureus-infected in vitro skin wounds. Staphylococcal sortase A enzyme and Arg systems are the targets of FlaB in bacterial cells. Nrf2/Bach1 dependent pro/antioxidant defense system is a target of FlaB in human cells. Some suggestions have also been made regarding the biological role of this marine fungal metabolite and its therapeutic possibilities.

Keywords:   Staphylococcus aureus ; antibiotics; antioxidants; marine fungi; secondary metabolites

DOI:  https://doi.org/10.1093/jambio/lxae318
Front Immunol. 2024 ;15 1513542

O-GlcNAcylation dictates pyroptosis.

Yue Lang, Jincheng Li, Leiliang Zhang.

  O-GlcNAcylation is a dynamic post-translational modification involving the attachment of N-acetylglucosamine to serine and threonine residues. This review emphasizes its role in regulating the signaling pathways of pyroptosis. Specifically, the O-GlcNAcylation of GSDMD is linked to the modulation of pyroptosis, suggesting that enhancing O-GlcNAcylation of GSDMD could be crucial for improving hypoperfusion in sepsis. Additionally, GSDME, another member of the gasdermin family, facilitates macrophage pyroptosis through O-GlcNAcylation induced by high glucose levels in the context of periodontitis. The review also examines the effects of O-GlcNAcylation on the NLRP3 inflammasome and its regulators, including NEK7 and NF-κB. Overall, this review emphasizes the role of O-GlcNAcylation in the pathogenesis of conditions such as sepsis, periodontitis, and osteoarthritis, identifying potential therapeutic targets for managing inflammatory responses through its targeted modulation.

Keywords:  GSDMD; GSDME; NLRP3; O-GlcNAcylation; pyroptosis

DOI:  https://doi.org/10.3389/fimmu.2024.1513542
Nat Microbiol. 2025 Jan 02.

Metagenomic immunoglobulin sequencing reveals IgA coating of microbial strains in the healthy human gut.

Matthew R Olm, Sean P Spencer, Tadashi Takeuchi, Evelyn Lemus Silva, Justin L Sonnenburg.

IgA, the primary human antibody secreted from the gut mucosa, shapes the intestinal microbiota. Methodological limitations have hindered defining which microbial strains are targeted by IgA and the implications of binding. Here we develop a technique, metagenomic immunoglobulin sequencing (MIg-seq), that provides strain-level resolution of microbes coated by IgA and use it to determine IgA coating levels for 3,520 gut microbiome strains in healthy human faeces. We find that both health and disease-associated bacteria are targeted by IgA. Microbial genes are highly predictive of IgA binding levels; in particular, mucus degradation genes are correlated with high binding, and replication rates are significantly reduced for microbes bound by IgA. We demonstrate that IgA binding is more correlated with host immune status than traditional relative abundance measures of microbial community composition. This study introduces a powerful technique for assessing strain-level IgA binding in human stool, paving the way for deeper understanding of IgA-based host-microbe interactions.

DOI: https://doi.org/10.1038/s41564-024-01887-4
Front Immunol. 2024 ;15 1468957

Hidden features: CD36/SR-B2, a master regulator of macrophage phenotype/function through metabolism.

Yuge Chen, Xuejia Zhang, Shengbin Huang, Maria Febbraio.

  Once thought to be in a terminally differentiated state, macrophages are now understood to be highly pliable, attuned and receptive to environmental cues that control and align responses. In development of purpose, the centrality of metabolic pathways has emerged. Thus, macrophage inflammatory or reparative phenotypes are tightly linked to catabolic and anabolic metabolism, with further fine tuning of specific gene expression patterns in specific settings. Single-cell transcriptome analyses have revealed a breadth of macrophage signatures, with some new influencers driving phenotype. CD36/Scavenger Receptor B2 has established roles in immunity and lipid metabolism. Macrophage CD36 is a key functional player in metabolic expression profiles that determine phenotype. Emerging data show that alterations in the microenvironment can recast metabolic pathways and modulate macrophage function, with the potential to be leveraged for therapeutic means. This review covers recent data on phenotypic characterization of homeostatic, atherosclerotic, lipid-, tumor- and metastatic-associated macrophages, with the integral role of CD36 highlighted.

Keywords:  CD36; SR-B2; atherosclerosis; macrophage metabolism; obesity; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1468957
Am J Physiol Lung Cell Mol Physiol. 2025 Jan 02.

mTOR Signaling Regulates Multiple Metabolic Pathways in Human Lung Fibroblasts After TGF-β and in Pulmonary Fibrosis.

Kun Woo D Shin, M Volkan Atalay, Rengul Cetin-Atalay, Erin M O'Leary, Mariel E Glass, Jennifer C Houpy Szafran, Parker S Woods, Angelo Y Meliton, Obada R Shamaa, Yufeng Tian, Gökhan M Mutlu, Robert B Hamanaka.

  Idiopathic pulmonary fibrosis is a fatal disease characterized by the TGF-β-dependent activation of lung fibroblasts, leading to excessive deposition of collagen proteins and progressive replacement of healthy lung with scar tissue. We and others have shown that TGF-β-mediated activation of the Mechanistic Target of Rapamycin Complex 1 (mTORC1) and downstream upregulation of Activating Transcription Factor 4 (ATF4) promote metabolic reprogramming in lung fibroblasts characterized by upregulation of the de novo synthesis of glycine, the most abundant amino acid found in collagen protein. Whether mTOR and ATF4 regulate other metabolic pathways in lung fibroblasts has not been explored. Here, we used RNA sequencing to determine how both ATF4 and mTOR regulate gene expression in human lung fibroblasts following TGF-β. We found that ATF4 primarily regulates enzymes and transporters involved in amino acid homeostasis as well as aminoacyl-tRNA synthetases. mTOR inhibition resulted not only in the loss of ATF4 target gene expression, but also in the reduced expression of glycolytic enzymes and mitochondrial electron transport chain subunits. Analysis of TGF-β-induced changes in cellular metabolite levels confirmed that ATF4 regulates amino acid homeostasis in lung fibroblasts while mTOR also regulates glycolytic and TCA cycle metabolites. We further analyzed publicly available single-cell RNA-seq data sets and found increased expression of ATF4 and mTOR-regulated genes in pathologic fibroblast populations from the lungs of IPF patients. Our results provide insight into the mechanisms of metabolic reprogramming in lung fibroblasts and highlight novel ATF4 and mTOR-dependent pathways that may be targeted to inhibit fibrotic processes.

Keywords:  ATF4; Fibrosis; Metabolism; mTOR

DOI:  https://doi.org/10.1152/ajplung.00189.2024
Cell Mol Life Sci. 2025 Jan 03. 82(1): 33

Establishment of nasal and olfactory epithelium organoids for unveiling mechanism of tissue regeneration and pathogenesis of nasal diseases.

Jinxia Liu, Yunfeng Zhang, Yiqun Yu.

  Organoid is an ideal in vitro model with cellular heterogeneity and genetic stability when passaging. Currently, organoids are exploited as new tools in a variety of preclinical researches and applications for disease modeling, drug screening, host-microbial interactions, and regenerative therapy. Advances have been made in the establishment of nasal and olfactory epithelium organoids that are used to investigate the pathogenesis of smell-related diseases and cellular/molecular mechanism underlying the regeneration of olfactory epithelium. A set of critical genes are identified to function in cell proliferation and neuronal differentiation in olfactory epithelium organoids. Besides, nasal epithelium organoids derived from chronic rhinosinusitis patients have been established to reveal the pathogenesis of this disease, potentially applied in drug responses in individual patient. The present article reviews recent research progresses of nasal and olfactory epithelium organoids in fundamental and preclinical researches, and proposes current advances and potential future direction in the field of organoid research and application.

Keywords:  Chronic rhinosinusitis; Nasal epithelium; Olfactory epithelium; Organoid; Regeneration

DOI:  https://doi.org/10.1007/s00018-024-05557-w
Trends Endocrinol Metab. 2024 Dec 31. pii: S1043-2760(24)00321-7. [Epub ahead of print]

Lipids guide T cell antitumor immunity by shaping their metabolic and functional fitness.

Letizia Rumiano, Teresa Manzo.

  Lipids are metabolic messengers essential for energy production, membrane structure, and signal transduction. Beyond their recognized role, lipids have emerged as metabolic rheostats of T cell responses, with distinct species differentially modulating CD8+ T cell (CTL) fate and function. Indeed, lipids can influence T cell signaling by altering their membrane composition; in addition, they can affect the differentiation path of T cells through cellular metabolism. This Review discusses the ability of lipids to shape T cell phenotypes and functions. Based on this link between lipid metabolism, metabolic fitness and immunosurveillance, we suggest that lipid could be rationally integrated in the context of immunotherapies to fine-tune fitness and function of adoptive T cell therapy (ACT) products.

Keywords:  CD8 T cells; antitumor immunity; immunotherapy; lipids; metabolism

DOI:  https://doi.org/10.1016/j.tem.2024.11.014
Am J Physiol Cell Physiol. 2024 Dec 31.

CD147 mitochondria translocation induced airway remodeling in asthmatic mouse models by regulating M2 macrophage polarization via ANT1-mediated mitophagy.

Guiyin Zhu, Haiyang Yu, Xiaoming Li, Wenjing Ye, Xi Chen, Wen Gu.

  CD147 has the potential to serve as a specific target with therapeutic characteristics in several respiratory diseases. Studies have demonstrated that CD147 regulates levels of oxidative phosphorylation (OXPHOS) through the process of mitochondrial translocations. However, there is still limited insight in the distinct mechanism of CD147 in asthmatic macrophages. Here, we found that CD147 expression levels increased significantly both in vivo and in vitro. CD147 undergoes mitochondrial translocation in M2 macrophages. Reducing the expression of CD147 resulted in a decline in M2 polarization levels within macrophages, as well as a decrease in the levels of mitochondrial respiratory chain complex I, II, and IV proteins. This effect may be attained by interacting with ANT1, subsequently impacting the levels of mitophagy. We also discovered that CD147 knockdown significantly reduced airway remodeling and inflammation in addition to lowering the polarization level of M2 in the lung tissues of chronic asthmatic model mice. The findings represent the first evidence of the distinct function of CD147 in the process of airway remodeling in asthma.

Keywords:  CD147; M2 polarization; airway remodeling; macrophages; mitochondrial translocation

DOI:  https://doi.org/10.1152/ajpcell.00735.2024
J Neurovirol. 2024 Dec 28.

Innate immune memory in chronic HIV and HIV-associated neurocognitive disorders (HAND): potential mechanisms and clinical implications.

Zachary Capriotti, Zachary Klase.

  Although antiretroviral therapy (ART) has dramatically improved the outlook of the HIV/AIDS pandemic, people living with HIV (PLWH) on suppressive therapy are still at higher risk for a range of comorbidities including cardiovascular disease (CVD) and HIV-associated neurocognitive disorders (HAND), among others. Chronic inflammation and immune activation are thought to be an underlying cause of these comorbidities. Many of the factors thought to drive chronic inflammation and immune activation in HIV overlap with factors known to induce trained immunity. Trained immunity is a form of innate immune memory that metabolically and epigenetically reprograms innate immune cells to mount enhanced inflammatory responses upon secondary encounter with unrelated inflammatory stimuli. While this phenotype has been characterized in a variety of disease states in animals and humans, very little is known about its potential contribution to chronic HIV pathogenesis. In this review, a broad overview of innate immune memory in the periphery and the central nervous system (CNS) is provided and the evidence for trained immunity in the context of HIV is considered. In PLWH on ART, this phenotype could contribute to the chronic inflammation and immune activation associated with HIV comorbidities and could complicate HIV cure strategies due to the potential persistence of the phenotype after eradication of the virus. Further research into this immune state in the context of HIV may open the door for new therapeutics aimed at treating HIV comorbidities like HAND.

Keywords:  Cytokines; HIV-associated neurocognitive disorders; Innate immune memory; Microglia; Monocytes; Neuroinflammation

DOI:  https://doi.org/10.1007/s13365-024-01239-2
Front Immunol. 2024 ;15 1491175

Revisiting surfactant protein D: an immune surveillance molecule bridging innate and adaptive immunity.

Azra Shamim, Mughair Abdul Aziz, Faryal Saeed, Rekha Kumari, Ann Mary Joseph, Pretty Ponnachan, Uday Kishore, Khaled Masmoudi.

  Surfactant protein D (SP-D) is a C-type lectin that was originally discovered as a lung surfactant associated phospholipid recognising protein. It was originally shown to be of great importance in surfactant turnover and homeostasis in conjunction with another hydrophilic surfactant protein i.e. SP-A. In addition, it was found to agglutinate bacteria in suspension and likely a key defence molecule in the lungs. Since its early days of characterization in 1990s, SP-D has turned out to be a central player in the mucosal immunity as pulmonary as well as extrapulmonary innate immune molecule. The most exciting development has been characterization of its C-type lectin or carbohydrate recognition domain (CRDs) that exists in a homotrimeric form in native as well as recombinant versions. SP-D has a range of strategies to recognise pathogen-associated molecular patterns (PAMPs) and thus act as a soluble PAMP-recognizing receptor (PRR), and subsequent destruction of the pathogens directly, or indirectly via phagocytic cells. SP-D also recognizes a range of allergens, competes out with specific IgE antibodies, and downregulates histamine release by basophils and mast cells. These anti-microbial and anti-allergic properties of SP-D have been validated by in vivo murine models of infection and allergy. The SP-D gene deficient mice exhibit remarkable phenotypes where lungs are leaky, showing features of fibrosis and emphysema. One of the seminal discoveries in the field has been the observation that activated eosinophils (and other immune cells) can be induced into apoptotic pathways by SP-D. This raised the possibility that SP-D can be an innate immune surveillance molecule. Studies have revealed the ability of a recombinant fragment of human SP-D containing homotrimeric neck and CRD region to induce apoptosis via intrinsic as well as extrinsic pathways; in addition, it also seems capable of interfering with epithelial-to-mesenchymal transition. These studies have opened up enormous possibilities for setting up pre-clinical and clinical trials.

Keywords:  PAMP; SP-D; allergens; apoptosis; cancer; innate immunity; lectin

DOI:  https://doi.org/10.3389/fimmu.2024.1491175
Nat Rev Cardiol. 2025 Jan 02.

Functional diversity of cardiac macrophages in health and disease.

Steven Yang, Vinay Penna, Kory J Lavine.

Macrophages make up a substantial portion of the stromal compartment of the heart in health and disease. In the past decade, the origins of these cardiac macrophages have been established as two broad populations derived from either embryonic or definitive haematopoiesis and that can be distinguished by the expression of CC-motif chemokine receptor 2 (CCR2). These cardiac macrophage populations are transcriptionally distinct and have differing cell surface markers and divergent roles in cardiac homeostasis and disease. Embryonic-derived CCR2- macrophages are a tissue-resident population that participates in tissue development, repair and maintenance, whereas CCR2+ macrophages are derived from definitive haematopoiesis and contribute to inflammation and tissue damage. Studies from the past 5 years have leveraged single-cell RNA sequencing technologies to expand our understanding of cardiac macrophage diversity, particularly of the monocyte-derived macrophage populations that reside in the injured and diseased heart. Emerging technologies in spatial transcriptomics have enabled the identification of distinct disease-associated cellular neighbourhoods consisting of macrophages, other immune cells and fibroblasts, highlighting the involvement of macrophages in cell-cell communication. Together, these discoveries lend new insights into the role of specific macrophage populations in the pathogenesis of cardiac disease, which can pave the way for the identification of new therapeutic targets and the development of diagnostic tools. In this Review, we discuss the developmental origin of cardiac macrophages and describe newly identified cell states and associated cellular neighbourhoods in the steady state and injury settings. We also discuss various contributions and effector functions of cardiac macrophages in homeostasis and disease.

DOI: https://doi.org/10.1038/s41569-024-01109-8
Front Endocrinol (Lausanne). 2024 ;15 1500772

Trained innate immunity as a potential link between preeclampsia and future cardiovascular disease.

Ivo Carrasco-Wong, Javiera M Sanchez, Jaime A Gutierrez, Delia I Chiarello.

  Preeclampsia (PE) is a complex pregnancy syndrome characterized by hypertension with or without proteinuria, affecting 2-6% of pregnancies globally. PE is characterized by excessive release of damage-associated molecular patterns (DAMPs) into the maternal circulation. This DAMP-rich milieu acts on innate immune cells, inducing a proinflammatory state characterized by elevated cytokines such as IL-1β and IL-18. This proinflammatory state in the mother and placenta results in the endothelial dysfunction strongly associated with cardiovascular disorders. While the immediate maternal and fetal risks of PE are well-documented, accumulating evidence indicates that PE also confers long-term cardiovascular risks to the mother, including hypertension, coronary heart disease, stroke, and heart failure. The underlying mechanisms connecting PE to these chronic cardiovascular conditions remain unclear. This article explores the potential role of trained innate immunity (TRIM) as a mechanistic link between PE and increased long-term cardiovascular risk. We propose that the persistent exposure to DAMPs during PE may epigenetically reprogram maternal innate immune cells and their progenitors, leading to TRIM. This reprogramming enhances the inflammatory response to subsequent stimuli, potentially contributing to endothelial dysfunction and chronic inflammation that predispose women to cardiovascular diseases later in life. Understanding the role of TRIM in PE could provide novel insights into the pathophysiology of PE-related cardiovascular complications and identify potential targets for therapeutic intervention. Further research is warranted to investigate the epigenetic and metabolic alterations in innate immune cells induced by PE and to determine how these changes may influence long-term maternal cardiovascular health.

Keywords:  DAMPs (damage-associated molecular pattern molecules); long-lasting effects; maternal cardiovascular health; preeclampsia; trained immunity

DOI:  https://doi.org/10.3389/fendo.2024.1500772
Signal Transduct Target Ther. 2025 Jan 03. 10(1): 2

In defence of ferroptosis.

Francesca Alves, Darius Lane, Triet Phu Minh Nguyen, Ashley I Bush, Scott Ayton.

Rampant phospholipid peroxidation initiated by iron causes ferroptosis unless this is restrained by cellular defences. Ferroptosis is increasingly implicated in a host of diseases, and unlike other cell death programs the physiological initiation of ferroptosis is conceived to occur not by an endogenous executioner, but by the withdrawal of cellular guardians that otherwise constantly oppose ferroptosis induction. Here, we profile key ferroptotic defence strategies including iron regulation, phospholipid modulation and enzymes and metabolite systems: glutathione reductase (GR), Ferroptosis suppressor protein 1 (FSP1), NAD(P)H Quinone Dehydrogenase 1 (NQO1), Dihydrofolate reductase (DHFR), retinal reductases and retinal dehydrogenases (RDH) and thioredoxin reductases (TR). A common thread uniting all key enzymes and metabolites that combat lipid peroxidation during ferroptosis is a dependence on a key cellular reductant, nicotinamide adenine dinucleotide phosphate (NADPH). We will outline how cells control central carbon metabolism to produce NADPH and necessary precursors to defend against ferroptosis. Subsequently we will discuss evidence for ferroptosis and NADPH dysregulation in different disease contexts including glucose-6-phosphate dehydrogenase deficiency, cancer and neurodegeneration. Finally, we discuss several anti-ferroptosis therapeutic strategies spanning the use of radical trapping agents, iron modulation and glutathione dependent redox support and highlight the current landscape of clinical trials focusing on ferroptosis.

DOI: https://doi.org/10.1038/s41392-024-02088-5
Nat Immunol. 2025 Jan;26(1): 29-41

Innate immune cells link dietary cues to normal and abnormal metabolic regulation.

Peng Zhang, Kosuke Watari, Michael Karin.

A slew of common metabolic disorders, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease and steatohepatitis, are exponentially increasing in our sedentary and overfed society. While macronutrients directly impact metabolism and bioenergetics, new evidence implicates immune cells as critical sensors of nutritional cues and important regulators of metabolic homeostasis. A deeper interrogation of the intricate and multipartite interactions between dietary components, immune cells and metabolically active tissues is needed for a better understanding of metabolic regulation and development of new treatments for common metabolic diseases. Responding to macronutrients and micronutrients, immune cells play pivotal roles in interorgan communication between the microbiota, small intestine, metabolically active cells including hepatocytes and adipocytes, and the brain, which controls feeding behavior and energy expenditure. This Review focuses on the response of myeloid cells and innate lymphocytes to dietary cues, their cross-regulatory interactions and roles in normal and aberrant metabolic control.

DOI: https://doi.org/10.1038/s41590-024-02037-y
mSphere. 2024 Dec 31. e0088324

A thermodynamic bottleneck in the TCA cycle contributes to acetate overflow in Staphylococcus aureus.

Nabia Shahreen, Jongsam Ahn, Adil Alsiyabi, Niaz Bahar Chowdhury, Dhananjay Shinde, Sujata S Chaudhari, Kenneth W Bayles, Vinai C Thomas, Rajib Saha.

  During aerobic growth, S. aureus relies on acetate overflow metabolism, a process where glucose is incompletely oxidized to acetate, for its bioenergetic needs. Acetate is not immediately captured as a carbon source and is excreted as waste by cells. The underlying factors governing acetate overflow in S. aureus have not been identified. Here, we show that acetate overflow is favored due to a thermodynamic bottleneck in the TCA cycle specifically involving the oxidation of succinate to fumarate by succinate dehydrogenase. This bottleneck reduces flux through the TCA cycle, making it more efficient for S. aureus to generate ATP via acetate overflow metabolism. Additionally, the protein allocation cost of maintaining ATP flux through the restricted TCA cycle is greater than that of acetate overflow metabolism. Finally, we show that the TCA cycle bottleneck provides S. aureus the flexibility to redirect carbon toward maintaining redox balance through lactate overflow when oxygen becomes limiting, albeit at the expense of ATP production through acetate overflow. Overall, our findings suggest that overflow metabolism offers S. aureus distinct bioenergetic advantages over a thermodynamically constrained TCA cycle, potentially supporting its commensal-pathogenic lifestyle.

Keywords:  acetate overflow; membrane crowding; overflow metabolism; redox imbalance; thermodynamic bottleneck

DOI:  https://doi.org/10.1128/msphere.00883-24
Nat Commun. 2024 Dec 30. 15(1): 10801

Cytokine-armed pyroptosis induces antitumor immunity against diverse types of tumors.

Sara Orehek, Taja Železnik Ramuta, Duško Lainšček, Špela Malenšek, Martin Šala, Mojca Benčina, Roman Jerala, Iva Hafner-Bratkovič.

Inflammasomes are defense complexes that utilize cytokines and immunogenic cell death (ICD) to stimulate the immune system against pathogens. Inspired by their dual action, we present cytokine-armed pyroptosis as a strategy for boosting immune response against diverse types of tumors. To induce pyroptosis, we utilize designed tightly regulated gasdermin D variants comprising different pore-forming capabilities and diverse modes of activation, representing a toolbox of ICD inducers. We demonstrate that the electrogenic transfer of ICD effector-encoding plasmids into mouse melanoma tumors when combined with intratumoral expression of cytokines IL-1β, IL-12, or IL-18, enhanced anti-tumor immune responses. Careful selection of immunostimulatory molecules is, however, imperative as a combination of IL-1β and IL-18 antagonized the protective effect of pyroptosis by IFNγ-mediated upregulation of several immunosuppressive pathways. Additionally, we show that the intratumoral introduction of armed pyroptosis provides protection against distant tumors and proves effective across various tumor types without inducing systemic inflammation. Deconstructed inflammasomes thus serve as a powerful, tunable, and tumor-agnostic strategy to enhance antitumor response, even against the most resilient types of tumors.

DOI: https://doi.org/10.1038/s41467-024-55083-3
Front Immunol. 2024 ;15 1463224

Metformin improves Mycobacterium avium infection by strengthening macrophage antimicrobial functions.

Sindre Dahl Mediaas, Markus Haug, Claire Louet, Sissel Gyrid Freim Wahl, Alexandre Gidon, Trude Helen Flo.

   Introduction: The incidence and prevalence of infections with non-tuberculous mycobacteria such as Mycobacterium avium (Mav) are increasing. Prolonged drug regimens, inherent antibiotic resistance, and low cure rates underscore the need for improved treatment, which may be achieved by combining standard chemotherapy with drugs targeting the host immune system. Here, we examined if the diabetes type 2 drug metformin could improve Mav-infection.
Methods: Metformin was administered to C57BL/6 mice infected intranasally with Mav and C57BL/6 mice were infected intranasally with Mav and treated with metformin over 3 weeks. Organ bacterial loads and lung pathology, inflammatory cytokines and immune cell profiles were assessed. For mechanistic insight, macrophages infected with Mav were treated with metformin alone or in combination with inhibitors for mitochondrial ROS or AMPK and assessed for bacterial burden and phagosome maturation.
Results and discussion: Three weeks of metformin treatment significantly reduced the lung mycobacterial burden in mice infected with Mav without major changes in the overall lung pathology or immune cell composition. Metformin treatment had no significant impact on tissue inflammation except for a tendency of increased lung IFNγ and infiltration of Mav-specific IFNγ-secreting T cells. Metformin did, however, boost the antimicrobial capacity of infected macrophages directly by modulating metabolism/activating AMPK, increasing mitochondrial ROS and phagosome maturation, and indirectly by bolstering type I immunity. Taken together, our data show that metformin improved the control of Mav-infection in mice, mainly by strengthening antimicrobial defenses in macrophages, and suggest that metformin has potential as an adjunct treatment of Mav infections.

Keywords:  Metformin; Mycobacterium avium; host-directed therapy; macrophage; mouse; non-tuberculous

DOI:  https://doi.org/10.3389/fimmu.2024.1463224