bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2025–03–09
forty-nine papers selected by
Chun-Chi Chang, Universitäts Spital Zürich
  1. The Integrated Pulmonary Immune Response to Pneumonia.
  2. Bioactive lipid signaling and lipidomics in macrophage polarization: Impact on inflammation and immune regulation.
  3. Trained immunity causes myeloid cell hypercoagulability.
  4. Editorial: Lung microbiome in health and disease.
  5. Elevated glucose increases methicillin-resistant Staphylococcus aureus antibiotic tolerance in a cystic fibrosis airway epithelial cell infection model.
  6. Mitochondria sense bacterial lactate and drive release of neutrophil extracellular traps.
  7. The molecular and metabolic landscape of ferroptosis in respiratory diseases: Pharmacological aspects.
  8. Interactions between bacteria in the human nasopharynx: a scoping review.
  9. Lactate in skin homeostasis: metabolism, skin barrier, and immunomodulation.
  10. Mutations in the Staphylococcus aureus Global Regulator CodY confer tolerance to an interspecies redox-active antimicrobial.
  11. Dendritic cells activate pyroptosis and effector-triggered apoptosis to restrict Legionella infection.
  12. Microbiota-derived extracellular vesicles: current knowledge, gaps, and challenges in precision nutrition.
  13. Modulation of M1 and M2 macrophage polarization by metformin: Implications for inflammatory diseases and malignant tumors.
  14. Innate immune training of osteoclastogenesis promotes inflammatory bone loss in mice.
  15. The gut-skin axis: a bi-directional, microbiota-driven relationship with therapeutic potential.
  16. Oxidative phosphorylation is a key feature of neonatal monocyte immunometabolism promoting myeloid differentiation after birth.
  17. Enterocloster clostridioformis protects against Salmonella pathogenesis and modulates epithelial and mucosal immune function.
  18. The lack of a biorepository during vaccine trials: A lost opportunity to understand staphylococcal immunity.
  19. Differential transcript and soluble factor patterns in macrophage/enterocyte-like monolayer co-cultures based on apical or basolateral LPS exposure.
  20. An engineered peptide derived from the innate immune effector High Mobility Group Box 1 disrupts and prevents dual genera biofilms formed by common respiratory tract pathogens.
  21. The tradeoffs between persistence and mutation rates at sub-inhibitory antibiotic concentrations in Staphylococcus aureus.
  22. Copper ions induces ferroptosis in Staphylococcus aureus and promotes healing of MRSA-induced wound infections.
  23. Functional hydrogels promote chronic infectious wound healing by re-rousing macrophage M1 and inducing bacterial copper-like death.
  24. Akkermansia muciniphila: promises and pitfallsfor next-generation beneficial microorganisms.
  25. The Interplay Between Innate Immunity and Nonimmune Cells in Lung Damage, Inflammation, and Repair.
  26. Deciphering respiratory viral infections by harnessing organ-on-chip technology to explore the gut-lung axis.
  27. Secreted factors of Aspergillus fumigatus cause lung epithelial barrier disruption: A study using an air-liquid interface cell culture model.
  28. Increased fatty acid production and macrophage-driven inflammation as key drivers of severe respiratory disease.
  29. Acute hypoxia modulate macrophage phenotype accompanied with transcriptome re-programming and metabolic re-modeling.
  30. TBK1 and IKKε prevent premature cell death by limiting the activity of both RIPK1 and NLRP3 death pathways.
  31. Lactylation and regulated cell death.
  32. Decreased levels and function of dendritic cells in blood and airways predict COVID-19 severity.
  33. Evaluating infection risk associated with Staphylococcus aureus nasal carriage in blood donors: a prospective multicentre study in Denmark.
  34. Cytometry at the Intersection of Metabolism and Epigenetics in Lymphocyte Dynamics.
  35. Applying 3D cultures and high-throughput technologies to study host-pathogen interactions.
  36. Absolute quantification of the living skin microbiome overcomes relic-DNA bias and reveals specific patterns across volunteers.
  37. Clinical isolates of antimicrobial resistant Enterobacter species can persist in human macrophages without replication and overt cellular cytotoxicity.
  38. An in vitro model demonstrating homeostatic interactions between reconstructed human gingiva and a saliva-derived multispecies biofilm.
  39. Molecules-mediated bidirectional interactions between microbes and human cells.
  40. TAK1 at the crossroads of multiple regulated cell death pathways: from molecular mechanisms to human diseases.
  41. Cell-autonomous innate immunity by proteasome-derived defence peptides.
  42. LA-peptide Hydrogel-Regulation of macrophage and fibroblast fates and their crosstalk via attenuating TGF-β to promote scarless wound healing.
  43. Epigenetic regulation of transcription factors involved in NLRP3 inflammasome and NF-kB signaling pathways.
  44. An antibody-toxin conjugate enhances innate immune cell responses in tumors.
  45. Spontaneous lung colonization in the cystic fibrosis rat model is linked to gastrointestinal obstruction.
  46. Single-cell analysis of CD14+CD16+ monocytes identifies a subpopulation with an enhanced migratory and inflammatory phenotype.
  47. Cross-Talk Between Signal Transduction Systems and Metabolic Networks in Bacterial Antibiotics Resistance and Tolerance.
  48. Gut Microbiome Regulation of Gut Hormone Secretion.
  49. Caspase-11 and NLRP3 exacerbate systemic Klebsiella infection through reducing mitochondrial ROS production.
  1. Annu Rev Immunol. 2025 Mar 04.
    The Integrated Pulmonary Immune Response to Pneumonia.
    Katrina E Traber, Joseph P Mizgerd.
      Pneumonia is an acute respiratory infection of the lower respiratory tract. The effectiveness of the host immune response determines the severity of infection, or whether pneumonia occurs at all. The lungs house both innate and adaptive immune systems, which integrate their activities to provide host defense that eliminates microbes and prevents lower respiratory infection from becoming severe. Professional immune cells in the lung, like macrophages and lymphocytes, work with lung constituents, like epithelial cells and fibroblasts, to optimize antimicrobial defense. The dynamics of the immune response during infection and the immune components contributing to defense are influenced by prior experiences with respiratory pathogens, remodeling lung immunity in ways that improve responses against subsequent infections. This review covers how innate and adaptive immune activities coordinate inside the lung to provide integrated and effective immune resistance against respiratory pathogens.
    DOI:  https://doi.org/10.1146/annurev-immunol-082323-031642
  2. Front Immunol. 2025 ;16 1550500
    Bioactive lipid signaling and lipidomics in macrophage polarization: Impact on inflammation and immune regulation.
    Juan P Rodríguez, Javier Casas, María A Balboa, Jesús Balsinde.
      Macrophages, crucial innate immune cells, defend against pathogens and resolve inflammation, maintaining tissue balance. They perform phagocytosis, present antigens to T cells, and bond innate and adaptive immunity through various activation states. Classical activation is associated with Th1 responses and interferon γ production, while alternative activation, induced by interleukin 4, is characterized by increased endocytosis, reduced secretion of pro-inflammatory cytokines, and roles in immunoregulation and tissue remodeling. Although these represent opposite extremes observed in vitro, the remarkable plasticity of macrophages allows for a wide spectrum of activation phenotypes that are complex to characterize experimentally. While the application of omics techniques has resulted in significant advances in the characterization of macrophage polarization, lipidomic studies have received lesser attention. Beyond their role as structural components and energy sources, lipids function as signaling molecules that regulate macrophage activation and polarization, thereby shaping immune responses. This work reviews the interaction between lipid signaling and macrophage polarization, exploring how lipid metabolism influences macrophage phenotype and function. These insights offer potential therapeutic strategies for immune-mediated diseases and inflammation-related disorders, including inflammaging.
    Keywords:  inflammaging; lipid remodeling; lipidomic profiling; macrophage phenotype; phospholipase a2 signaling
    DOI:  https://doi.org/10.3389/fimmu.2025.1550500
  3. Sci Adv. 2025 Mar 07. 11(10): eads0105
    Trained immunity causes myeloid cell hypercoagulability.
    Aisling M Rehill, Seán McCluskey, Anna E Ledwith, Tristram A J Ryan, Betül Ünlü, Gemma Leon, Hugo Charles-Messance, Edmund H Gilbert, Paula Klavina, Emily A Day, Judith Coppinger, Jamie M O'Sullivan, Corrina McMahon, James S O'Donnell, Annie M Curtis, Luke A J O'Neill, Frederick J Sheedy, Roger J S Preston.
      The pathogenic basis for increased thrombotic risk in individuals with inflammatory diseases is poorly understood. Myeloid cell "trained immunity" describes persistent innate immune cell memory arising from prior exposure to an inflammatory stimulus, leading to an enhanced immune response to subsequent unrelated stimuli. We identify enhanced myeloid cell prothrombotic activity as a maladaptive consequence of trained immunity. Lipopolysaccharide (LPS) stimulation of macrophages trained previously with β-glucan or heme exhibited significantly enhanced procoagulant activity compared to macrophages stimulated with LPS alone, which was mediated by enhanced acid sphingomyelinase-mediated tissue factor decryption. Furthermore, splenic monocytes isolated from β-glucan-trained mice revealed enhanced procoagulant activity up to 4 weeks after β-glucan administration compared to monocytes from control mice over the same time period. Moreover, hematopoietic progenitor cells and bone marrow interstitial fluid from β-glucan-trained mice had enhanced procoagulant activity compared to control mice. Trained immunity and associated metabolic perturbations may therefore represent an opportunity for targeted intervention in immunothrombotic disease development.
    DOI:  https://doi.org/10.1126/sciadv.ads0105
  4. Front Pharmacol. 2025 ;16 1565849
    Editorial: Lung microbiome in health and disease.
    Kurtis Francis Budden, Luigina Romani.
      
    Keywords:  immunity; immunomodulation; lung diseases; metabolites; microbiota
    DOI:  https://doi.org/10.3389/fphar.2025.1565849
  5. Res Sq. 2025 Feb 17. pii: rs.3.rs-5938603. [Epub ahead of print]
    Elevated glucose increases methicillin-resistant Staphylococcus aureus antibiotic tolerance in a cystic fibrosis airway epithelial cell infection model.
    Emily M Hughes, Meghan J Hirsch, Joshua T Huffines, Stefanie Krick, Megan R Kiedrowski.
       BACKGROUND: In a healthy lung, the airway epithelium regulates glucose transport to maintain low glucose concentrations in the airway surface liquid (ASL). However, hyperglycemia and chronic lung diseases, such as cystic fibrosis (CF), can result in increased glucose in bronchial aspirates. People with CF are also at increased risk of lung infections caused by bacterial pathogens, including methicillin-resistant Staphylococcus aureus. Yet, it is not known how increased airway glucose availability affects bacteria in chronic CF lung infections or impacts treatment outcomes.
    METHODS: To model the CF airways, we cultured immortalized CF (CFBE41o-) and non-CF (16HBE) human bronchial epithelial cells at air liquid interface (ALI). Glucose concentrations in the basolateral media were maintained at 5.5 mM or 12.5 mM, to mimic a normal and hyperglycemic milieu respectively. 2-deoxyglucose was added to high glucose culture media to restrict glucose availability. We collected ASL, basolateral media, and RNA from ALI cultures to assess the effects of elevated glucose. We also inoculated S. aureus onto the apical surface of normal or high glucose ALI cultures and observed the results of antibiotic treatment post-inoculation. S. aureus growth was measured by enumerating viable colony forming units (CFU) and with fluorescence microscopy. The effects of elevated glucose on in vitro growth and antibiotic treatment were also evaluated in standard bacterial culture medium and synthetic CF medium (SCFM).
    RESULTS: We found that glucose concentrations in the ASL of ALI cultures maintained in normal or high glucose mimicked levels measured in breath condensate assays from people with CF and hyperglycemia. Additionally, we found hyperglycemia increased S. aureus aggregation and antibiotic resistance during infection of cells maintained in high glucose compared to normal glucose conditions. Heightened antibiotic tolerance or resistance as not observed during in vitro growth with elevated glucose. Limiting glucose with 2-deoxyglucose both decreased aggregation and reduced antibiotic resistance back to levels comparable to non-hyperglycemic conditions.
    CONCLUSIONS: These data indicate hyperglycemia alters S. aureus growth during infection and may reduce efficacy of antibiotic treatment. Glucose restriction is a potential option that could be explored to limit bacterial growth and improve treatment outcomes in chronic airway infections.
    DOI:  https://doi.org/10.21203/rs.3.rs-5938603/v1
  6. Cell Host Microbe. 2025 Feb 20. pii: S1931-3128(25)00051-4. [Epub ahead of print]
    Mitochondria sense bacterial lactate and drive release of neutrophil extracellular traps.
    Ashley D Wise, Eden G TenBarge, Jessica D C Mendonça, Ellie C Mennen, Sarah R McDaniel, Callista P Reber, Bailey E Holder, Madison L Bunch, Eva Belevska, Madalyn G Marshall, Nicole M Vaccaro, Christian R Blakely, Dinesh H Wellawa, Jennifer Ferris, Jessica R Sheldon, Jeffry D Bieber, Jeremiah G Johnson, Lindsey R Burcham, Andrew J Monteith.
      Neutrophils induce oxidative stress, creating a harsh phagosomal environment. However, Staphylococcus aureus can survive these conditions, requiring neutrophils to deploy mechanisms that sense bacterial persistence. We find that staphylococcal lactate is a metabolic danger signal that triggers neutrophil extracellular trap release (NETosis). Neutrophils coordinate mitochondria in proximity to S. aureus-containing phagosomes, allowing transfer of staphylococcal lactate to mitochondria where it is rapidly converted into pyruvate and causes mitochondrial reactive oxygen species, a precursor to NETosis. Similar results were observed in response to phylogenetically distinct bacteria, implicating lactate accumulation as a broad signal triggering NETosis. Furthermore, patients with systemic lupus erythematosus (SLE) are more susceptible to bacterial infections. We find that SLE neutrophils cannot sense bacterial lactate impairing their capacity to undergo NETosis upon S. aureus infection but initiate aberrant NETosis triggered by apoptotic debris. Thus, neutrophils adapt mitochondria as sensory organelles that detect bacterial metabolic activity and dictate downstream antibacterial processes.
    Keywords:  NETosis; Staphylococcus aureus; lactate; lactate dehydrogenase; mitochondria; neutrophil extracellular traps; neutrophils; phagosome; reverse electron trasport; systemic lupus erythematosus
    DOI:  https://doi.org/10.1016/j.chom.2025.02.003
  7. J Pharm Anal. 2025 Jan;15(1): 101050
    The molecular and metabolic landscape of ferroptosis in respiratory diseases: Pharmacological aspects.
    Tong Wu, Miaorong Ji, Tian Li, Lianxiang Luo.
      Ferroptosis is a form of cell death that occurs when there is an excess of reactive oxygen species (ROS), lipid peroxidation, and iron accumulation. The precise regulation of metabolic pathways, including iron, lipid, and amino acid metabolism, is crucial for cell survival. This type of cell death, which is associated with oxidative stress, is controlled by a complex network of signaling molecules and pathways. It is also implicated in various respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), lung cancer, pulmonary fibrosis (PF), and the coronavirus disease 2019 (COVID-19). To combat drug resistance, it is important to identify appropriate biological markers and treatment targets, as well as intervene in respiratory disorders to either induce or prevent ferroptosis. The focus is on the role of ferroptosis in the development of respiratory diseases and the potential of targeting ferroptosis for prevention and treatment. The review also explores the interaction between immune cell ferroptosis and inflammatory mediators in respiratory diseases, aiming to provide more effective strategies for managing cellular ferroptosis and respiratory disorders.
    Keywords:  Antioxidant mechanism; Ferroptosis; Iron metabolism; Lipid peroxidation; Respiratory diseases
    DOI:  https://doi.org/10.1016/j.jpha.2024.101050
  8. Lancet Microbe. 2025 Mar 03. pii: S2666-5247(24)00330-6. [Epub ahead of print] 101062
    Interactions between bacteria in the human nasopharynx: a scoping review.
    Kan Yu, Vanessa Tenaglia, Eng Guan Chua, Robbie Haines, Girish Bahal, Mark P Nicol, Ritika Kar Bahal.
      Emerging evidence indicates that interactions between bacteria shape the nasopharyngeal microbiome and influence respiratory health. This Review uses the systematic scoping methodology to summarise 88 studies including observational and experimental studies, identifying key interactions between bacteria that colonise the human nasopharynx. A range of bacterial interactions were reported in the observational studies, including a variable association between Streptococcus pneumoniae and Haemophilus influenzae, a consistent positive association between S pneumoniae and Moraxella catarrhalis, and a consistent negative association between S pneumoniae and Staphylococcus aureus. Experimental studies largely validated the associations reported in the observational studies and provided insights into the mechanism and direction of interactions. In the context of respiratory health, non-pneumococcal alpha-haemolytic streptococci and the Gram-positive commensals Dolosigranulum and Corynebacterium inhibited respiratory pathogens such as H influenzae, S pneumoniae, M catarrhalis, and S aureus. These findings underscore how bacterial competition and coexistence shape the microbiome composition in this niche. This study has relevance for respiratory health and can be helpful for informing the design of potential microbiota-targeted therapies.
    DOI:  https://doi.org/10.1016/j.lanmic.2024.101062
  9. Front Immunol. 2025 ;16 1510559
    Lactate in skin homeostasis: metabolism, skin barrier, and immunomodulation.
    Dandan Ruan, Tingting Hu, Xuefan Yang, Xiaohui Mo, Qiang Ju.
      Lactate, once considered merely a byproduct of glycolysis, is now increasingly recognized as a multifunctional signaling molecule with roles beyond energy metabolism. It functions as an enzyme cofactor and binds to specific receptors to modulate cellular functions. In the skin, lactate is produced by various cell types. It is then transferred between cells or to the extracellular space, helping to balance cellular pH and to provide signals that regulate skin barrier and skin immunity. Additionally, lactate/lactate-related genes hold promising therapeutic potential for the treatment of skin tumors, inflammatory skin diseases, hair loss, and in cosmetic dermatology. This article highlights the latest advances in our understanding of lactate's biological effects on the skin and explores its therapeutic potential, offering insights into future research directions.
    Keywords:  immunomodulation; lactate; metabolism; skin barrier; therapeutics
    DOI:  https://doi.org/10.3389/fimmu.2025.1510559
  10. PLoS Genet. 2025 Mar 07. 21(3): e1011610
    Mutations in the Staphylococcus aureus Global Regulator CodY confer tolerance to an interspecies redox-active antimicrobial.
    Anthony M Martini, Sara A Alexander, Anupama Khare.
      Bacteria often exist in multispecies communities where interactions among different species can modify individual fitness and behavior. Although many competitive interactions have been described, molecular adaptations that can counter this antagonism and preserve or increase fitness remain underexplored. Here, we characterize the adaptation of Staphylococcus aureus to pyocyanin, a redox-active interspecies antimicrobial produced by Pseudomonas aeruginosa, a co-infecting pathogen frequently isolated from wound and chronic lung infections with S. aureus. Using experimental evolution, we identified mutations in a conserved global transcriptional regulator, CodY, that confer tolerance to pyocyanin and thereby enhance survival of S. aureus. A pyocyanin tolerant CodY mutant also had a survival advantage in co-culture with P. aeruginosa, likely through tolerance specifically to pyocyanin. The transcriptional response of the CodY mutant to pyocyanin indicated a two-pronged defensive response compared to the wild type. First, the CodY mutant strongly suppressed metabolism, by downregulating pathways associated with core metabolism, especially translation-associated genes, upon exposure to pyocyanin. Metabolic suppression via ATP depletion was sufficient to provide comparable protection against pyocyanin to the wild-type strain. Second, while both the wild-type and CodY mutant strains upregulated oxidative stress response pathways upon pyocyanin exposure, the CodY mutant overexpressed multiple stress response genes compared to the wild type. We determined that catalase overexpression was critical to pyocyanin tolerance as its absence eliminated tolerance in the CodY mutant and overexpression of catalase was sufficient to impart tolerance to the wild-type strain against purified pyocyanin and in co-culture with WT P. aeruginosa. Together, these results suggest that both transcriptional responses of reduced metabolism and an increased oxidative stress response likely contribute to pyocyanin tolerance in the CodY mutant. Our data thus provide new mechanistic insight into adaptation toward interbacterial antagonism via altered regulation that facilitates multifaceted protective cellular responses.
    DOI:  https://doi.org/10.1371/journal.pgen.1011610
  11. bioRxiv. 2025 Feb 17. pii: 2025.02.13.638189. [Epub ahead of print]
    Dendritic cells activate pyroptosis and effector-triggered apoptosis to restrict Legionella infection.
    Víctor R Vázquez Marrero, Jessica Doerner, Kimberly A Wodzanowski, Jenna Zhang, Allyson Lu, Frankie D Boyer, Isabel Vargas, Suzana Hossain, Karly B Kammann, Madison V Dresler, Sunny Shin.
      The innate immune system relies on pattern recognition receptors (PRRs) to detect pathogen-associated molecular patterns (PAMPs) and guard proteins to monitor pathogen disruption of host cell processes. How different immune cell types engage PRR- and guard protein-dependent defenses in response to infection is poorly understood. Here, we show that macrophages and dendritic cells (DCs) respond in distinct ways to bacterial virulence activities. In macrophages, the bacterial pathogen Legionella pneumophila deploys its Dot/Icm type IV secretion system (T4SS) to deliver effector proteins that facilitate its robust intracellular replication. In contrast, T4SS activity triggers rapid DC death that potently restricts Legionella replication within this cell type. Intriguingly, we found that infected DCs exhibit considerable heterogeneity at the single cell level. Initially, a subset of DCs activate caspase-11 and NLRP3 inflammasome-dependent pyroptosis and release IL-1 β early during infection. At later timepoints, a separate DC population undergoes apoptosis driven by T4SS effectors that block host protein synthesis, thereby depleting the levels of the pro-survival proteins Mcl-1 and cFLIP. Together, pyroptosis and effector-triggered apoptosis robustly restrict Legionella replication in DCs. Collectively, our work suggests a model where Mcl-1 and cFLIP guard host translation in DCs, and that macrophages and DCs distinctly employ innate immune sensors and guard proteins to mount divergent responses to Legionella infection.
    DOI:  https://doi.org/10.1101/2025.02.13.638189
  12. Front Immunol. 2025 ;16 1514726
    Microbiota-derived extracellular vesicles: current knowledge, gaps, and challenges in precision nutrition.
    Elvira Marquez-Paradas, Maria Torrecillas-Lopez, Luna Barrera-Chamorro, Jose L Del Rio-Vazquez, Teresa Gonzalez-de la Rosa, Sergio Montserrat-de la Paz.
      The gut microbiota has co-evolved with its host, profoundly shaping the development and functioning of the immune system. This co-evolution has led to a dynamic relationship where microbial metabolites and molecular signals influence immune maturation, tolerance, and defense mechanisms, highlighting its essential role in maintaining host health. Recently, bacterial extracellular vesicles (BEVs), membrane nanoparticles produced by bacteria, have emerged as important players in gut balance and as potent immune modulators. These vesicles reflect the characteristics of the bacterial membrane and contain nucleic acids, proteins, lipids, and metabolites. They can regulate immune processes and are involved in neurological and metabolic diseases due to their ability to distribute both locally in the gut and systemically, affecting immune responses at both levels. This review provides a comprehensive overview of the characteristics and functional profile of BEVs, detailing how nutrition influences the production and function of these vesicles, how antibiotics can disrupt or alter their composition, and how these factors collectively impact immunity and disease development. It also highlights the potential of BEVs in the development of precision nutritional strategies through dietary modulation, such as incorporating prebiotic fibers to enhance beneficial BEV production, reducing intake of processed foods that may promote harmful BEVs, and tailoring probiotic interventions to influence specific microbial communities and their vesicular outputs.
    Keywords:  diet; gut microbiota; gut-brain-axis; immunity; immunonutrition
    DOI:  https://doi.org/10.3389/fimmu.2025.1514726
  13. Int Immunopharmacol. 2025 Mar 01. pii: S1567-5769(25)00335-2. [Epub ahead of print]151 114345
    Modulation of M1 and M2 macrophage polarization by metformin: Implications for inflammatory diseases and malignant tumors.
    Sara Jafarzadeh, Maryam Nemati, Raziyeh Zandvakili, Abdollah Jafarzadeh.
      Macrophages perform an essential role in the body's defense mechanisms and tissue homeostasis. These cells exhibit plasticity and are categorized into two phenotypes, including classically activated/M1 pro-inflammatory and alternatively activated/M2 anti-inflammatory phenotypes. Functional deviation in macrophage polarization occurs in different pathological conditions that need correction. In addition to antidiabetic impacts, metformin also possesses multiple biological activities, including immunomodulatory, anti-inflammatory, anti-tumorigenic, anti-aging, cardioprotective, hepatoprotective, and tissue-regenerative properties. Metformin can influence the polarization of macrophages toward M1 and M2 phenotypes. The ability of metformin to support M2 polarization and suppress M1 polarization could enhance its anti-inflammatory properties and potentiate its protective effects in conditions such as chronic inflammatory diseases, atherosclerosis, and obesity. However, in metformin-treated tumors, the proportion of M2 macrophages is decreased, while the frequency ratio of M1 macrophages is increased, indicating that metformin can modulate macrophage polarization from a pro-tumoral M2 state to an anti-tumoral M1 phenotype in malignancies. Metformin affects macrophage polarization through AMPK-dependent and independent pathways involving factors, such as NF-κB, mTOR, ATF, AKT/AS160, SIRT1, STAT3, HO-1, PGC-1α/PPAR-γ, and NLRP3 inflammasome. By modulating cellular metabolism and apoptosis, metformin can also influence macrophage polarization. This review provides comprehensive evidence regarding metformin's effects on macrophage polarization and the underlying mechanisms. The polarization-inducing capabilities of metformin may provide significant therapeutic applications in various inflammatory diseases and malignant tumors.
    Keywords:  Atherosclerosis; Inflammation; M1/M2 macrophages; Macrophages; Malignant tumors; Metformin
    DOI:  https://doi.org/10.1016/j.intimp.2025.114345
  14. Dev Cell. 2025 Feb 19. pii: S1534-5807(25)00063-2. [Epub ahead of print]
    Innate immune training of osteoclastogenesis promotes inflammatory bone loss in mice.
    Nora Haacke, Hui Wang, Shu Yan, Marko Barovic, Xiaofei Li, Kosuke Nagai, Adelina Botezatu, Aikaterini Hatzioannou, Bettina Gercken, Giulia Trimaglio, Anisha U Shah, Jun Wang, Ling Ye, Mangesh T Jaykar, Martina Rauner, Ben Wielockx, Kyoung-Jin Chung, Mihai G Netea, Lydia Kalafati, George Hajishengallis, Triantafyllos Chavakis.
      We previously demonstrated that long-term trained immunity (TRIM) involves adaptations that imprint innate immune memory in long-lived myelopoiesis precursors and their progeny, monocytes/macrophages and neutrophils, which thereby acquire enhanced responsiveness to future challenges. Here, we show that a distinct component of myeloid biology, osteoclastogenesis, can also undergo innate immune training. Indeed, β-glucan-induced TRIM was associated with an increased osteoclastogenesis bias in the bone marrow and an expansion of monocytes/osteoclast progenitors in the periphery, resulting in aggravated severity of experimental periodontitis and arthritis. In the setting of trained inflammatory osteoclastogenesis, we observed transcriptomic rewiring in synovial myeloid cells of arthritic mice, featuring prominent upregulation of the transcription factor melanogenesis-associated transcription factor (MITF). Adoptive transfer of splenic monocytes from β-glucan-trained mice to naive recipients exacerbated arthritis in the latter in a strictly MITF-dependent manner. Our findings establish trained osteoclastogenesis as a maladaptive component of TRIM and potentially provide therapeutic targets in inflammatory bone loss disorders.
    Keywords:  inflammatory bone loss; innate immune memory; monocytes; osteoclastogenesis; trained immunity
    DOI:  https://doi.org/10.1016/j.devcel.2025.02.001
  15. Gut Microbes. 2025 Dec;17(1): 2473524
    The gut-skin axis: a bi-directional, microbiota-driven relationship with therapeutic potential.
    Maira Jimenez-Sanchez, Larissa S Celiberto, Hyungjun Yang, Ho Pan Sham, Bruce A Vallance.
      This review explores the emerging term "gut-skin axis" (GSA), describing the bidirectional signaling that occurs between the skin and the gastrointestinal tract under both homeostatic and disease conditions. Central to GSA communication are the gut and skin microbiota, the microbial communities that colonize these barrier surfaces. By influencing diverse host pathways, including innate immune, vitamin D receptor, and Aryl hydrocarbon receptor signaling, a balanced microbiota contributes to both tissue homeostasis and host defense. In contrast, microbiota imbalance, or dysbiosis at one site, can lead to local barrier dysfunction, resulting in the activation of signaling pathways that can disrupt tissue homeostasis at the other site, potentially leading to inflammatory skin conditions such as atopic dermatitis and psoriasis, or gut diseases like Inflammatory Bowel Disease. To date, most research on the GSA has examined the impact of the gut microbiota and diet on skin health, but recent studies show that exposing the skin to ultraviolet B-light can beneficially modulate both the gut microbiome and intestinal health. Thus, despite the traditional focus of clinicians and researchers on these organ systems as distinct, the GSA offers new opportunities to better understand the pathogenesis of cutaneous and gastrointestinal diseases and promote health at both sites.
    Keywords:  Gut-skin axis (GSA); cutaneous diseases; gastrointestinal diseases; gut and skin microbiota; ultraviolet B-light exposure
    DOI:  https://doi.org/10.1080/19490976.2025.2473524
  16. Nat Commun. 2025 Mar 06. 16(1): 2239
    Oxidative phosphorylation is a key feature of neonatal monocyte immunometabolism promoting myeloid differentiation after birth.
    Greta Ehlers, Annika Marie Tödtmann, Lisa Holsten, Maike Willers, Julia Heckmann, Jennifer Schöning, Maximilian Richter, Anna Sophie Heinemann, Sabine Pirr, Alexander Heinz, Christian Dopfer, Kristian Händler, Matthias Becker, Johanna Büchel, Achim Wöckel, Constantin von Kaisenberg, Gesine Hansen, Karsten Hiller, Joachim L Schultze, Christoph Härtel, Wolfgang Kastenmüller, Martin Vaeth, Thomas Ulas, Dorothee Viemann.
      Neonates primarily rely on innate immune defense, yet their inflammatory responses are usually restricted compared to adults. This is controversially interpreted as a sign of immaturity or essential programming, increasing or decreasing the risk of sepsis, respectively. Here, combined transcriptomic, metabolic, and immunological studies in monocytes of healthy individuals reveal an inverse ontogenetic shift in metabolic pathway activities with increasing age. Neonatal monocytes are characterized by enhanced oxidative phosphorylation supporting ongoing myeloid differentiation. This phenotype is gradually replaced during early childhood by increasing glycolytic activity fueling the inflammatory responsiveness. Microbial stimulation shifts neonatal monocytes to an adult-like metabolism, whereas ketogenic diet in adults mimicking neonatal ketosis cannot revive a neonate-like metabolism. Our findings disclose hallmarks of innate immunometabolism during healthy postnatal immune adaptation and suggest that premature activation of glycolysis in neonates might increase their risk of sepsis by impairing myeloid differentiation and promoting hyperinflammation.
    DOI:  https://doi.org/10.1038/s41467-025-57357-w
  17. Microbiome. 2025 Feb 28. 13(1): 61
    Enterocloster clostridioformis protects against Salmonella pathogenesis and modulates epithelial and mucosal immune function.
    Benjamin S Beresford-Jones, Satoshi Suyama, Simon Clare, Amelia Soderholm, Wangmingyu Xia, Puspendu Sardar, Junhee Lee, Katherine Harcourt, Trevor D Lawley, Virginia A Pedicord.
       BACKGROUND: Promoting resistance to enteric pathogen infection is a core function of the gut microbiota; however, many of the specific host-commensal interactions that mediate this protection remain uncharacterised. To address this knowledge gap, we monocolonised germ-free mice with mouse-derived commensal microbes to screen for microbiota-induced resistance to Salmonella Typhimurium infection.
    RESULTS: We identified Enterocloster clostridioformis as a protective species against S. Typhimurium infection. E. clostridioformis selectively upregulates resistin-like molecule β and cell cycle pathway expression at the level of caecal epithelial cells and increases T-regulatory cells in the underlying mucosal immune system, potentially contributing to reduced infection-induced pathology.
    CONCLUSIONS: We highlight novel mechanisms of host-microbe interactions that can mediate microbiota-induced resistance to acute salmonellosis. In the backdrop of increasing antibiotic resistance, this study identifies novel potential avenues for further research into protective host responses against enteric infections and could lead to new therapeutic approaches. Video Abstract.
    Keywords:   Enterocloster clostridioformis ; Escherichia coli ; Acute salmonellosis; Host–commensal interactions; Microbiota; Mouse models; Pathogen resistance; Resistin-like molecule β; Screen; T-regulatory cells
    DOI:  https://doi.org/10.1186/s40168-025-02050-9
  18. Vaccine. 2025 Mar 05. pii: S0264-410X(25)00193-8. [Epub ahead of print]53 126896
    The lack of a biorepository during vaccine trials: A lost opportunity to understand staphylococcal immunity.
    Richard A Proctor, Annette M Jackson, Vance G Fowler.
      Development of a vaccine against Staphylococcus aureus has proven to be difficult, in no small measure due to our lack of understanding of the human immune response to this pathogen. Because the human immune response is distinct from other species often used for pre-clinical animal models, including non-human primates, it will be necessary to perform studies in humans to guide vaccine development. One can view the staphylococcal vaccine clinical trials as an opportunity to study human immune response to S. aureus infections, which of course provide outcome data. In order to gain maximal information from these clinical trials, biological materials should be taken during the trial. In this commentary article, we explore a mechanism for such collection.
    Keywords:  Biomarker; Biorepository; Clinical trails; Human immunity; Staphylococcus aureus; Vaccine
    DOI:  https://doi.org/10.1016/j.vaccine.2025.126896
  19. Front Immunol. 2025 ;16 1527007
    Differential transcript and soluble factor patterns in macrophage/enterocyte-like monolayer co-cultures based on apical or basolateral LPS exposure.
    Aurora Mazzei, Martina Cucchiara, Lorenzo Mortara, Elena Bossi, Roberta Schiavone, Tiziano Verri, Antonino Bruno, Amilcare Barca.
       Background: The monolayer of intestinal epithelial cells (IECs) plays a crucial role in controlling intestinal homeostasis, also by its interaction with the immune system, via paracrine cytokine production, thus driving innate responses by tissue-resident immune cells. Here, using a co-culture model, we investigated the interactions between differentiated Caco-2 cells in monolayer and macrophages, by mimicking the cross-talk between enterocytes and immune cells during gastrointestinal (GI) tract inflammation.
    Methods: Caco-2 mature monolayers grown on Transwell membranes were challenged with apical or basolateral LPS. After stimulations, the enterocyte-like monolayers were transferred in co-culture with THP-1 derived macrophages. The functional impact of treatments was evaluated in terms of monolayer's permeability, expression of mRNAs related to inflammation and immune responses and analysis of immune soluble factors present in the co-culture media.
    Results: LPS effectively affected monolayer's permeability and induced a pro-inflammatory transcriptional program in Caco-2 monolayers. Remarkably, THP-1 derived macrophages differentially responded based on the diverse directional source of LPS, previously administered to the Caco-2 monolayers. Basolateral sensing of LPS, by Caco-2 monolayers, induced specific increase of several pro-inflammatory factors such as NF-kB1, IL-6 and IL-8, at transcript level, in macrophages, while apical sensing triggering targeted increase of IL-1β expression. Significantly, the analysis of immune factors secreted in the co-culture media suggested that paracrine interactions between enterocyte-like monolayers and macrophages are differently driven based on the basolateral vs. apical inflammation, previously triggered by LPS against the epithelial monolayer, and thus involving different immune gene networks.
    Conclusions: Taken together, our results suggest a framework of interactions between IECs and macrophages, depending upon the "polarized" inflammatory dysregulation.
    Keywords:  Caco-2 monolayer; IBD; LPS; THP-1 macrophages; inflammatory pathways
    DOI:  https://doi.org/10.3389/fimmu.2025.1527007
  20. FEMS Microbiol Lett. 2025 Feb 27. pii: fnaf029. [Epub ahead of print]
    An engineered peptide derived from the innate immune effector High Mobility Group Box 1 disrupts and prevents dual genera biofilms formed by common respiratory tract pathogens.
    Jaime D Rhodes, Tyler J Kelly, Steven D Goodman, Lauren O Bakaletz.
      Bacterial biofilms mediate chronic and recurrent bacterial infections that are extremely difficult to treat by currently available standards of care. In nature, these encased bacterial communities are typically comprised of more than one genus or species. Specifically, in the airway, nontypeable Haemophilus influenzae (NTHI) predominates and is commonly isolated with one or more of the following co-pathogens with which it forms unique relationships: methicillin-resistant Staphylococcus aureus, Burkholderia cenocepacia, Pseudomonas aeruginosa, Streptococcus pneumoniae, and Moraxella catarrhalis. We recently showed that dual genera biofilms comprised of NTHI plus a co-pathogen are disrupted when the biofilm matrix is destabilized by a pathogen-directed strategy that uses a humanized monoclonal antibody directed against the protective domains of bacterial DNABII proteins found at vertices of crossed strands of eDNA within the biofilm matrix. We also recently showed that a peptide synthesized from the host innate immune effector HMGB1, called mB Box-97syn, competitively inhibits binding of the bacterial DNABII proteins to eDNA which thereby also destabilizes single species biofilms to release biofilm-resident bacteria into a transient yet highly vulnerable state that is more effectively cleared by the host innate immune system and/or antibiotics. Here, we expanded upon these studies to assess the ability of host-augmenting mB Box-97syn to both disrupt 2-genera biofilms formed by NTHI plus a common co-pathogen, as well as prevent their formation. Disruption of established 2-genera biofilms ranged from 57-88%, whereas prevention of 2-genera biofilm formation ranged from 65-80% (P=0.002 - P<0.0001). The sobering recalcitrance of chronic and recurrent respiratory tract infections, combined with growing global concern about AMR, demands development of more effective management and prevention options. Ideally, novel treatment strategies would both target the pathogens and augment the host's natural abilities to eradicate them. Herein, we provide additional data to support continued development of the latter concept via demonstration of mB Box-97syn's efficacy against polymicrobial biofilms.
    Keywords:   Burkholderia cenocepacia ; High Mobility Group Box 1; Nontypeable Haemophilus influenzae [NTHI]; infection; methicillin-resistant Staphylococcus aureus [MRSA]; polymicrobial
    DOI:  https://doi.org/10.1093/femsle/fnaf029
  21. Microbiol Spectr. 2025 Mar 04. e0247924
    The tradeoffs between persistence and mutation rates at sub-inhibitory antibiotic concentrations in Staphylococcus aureus.
    Alysha S Ismail, Brandon A Berryhill, Teresa Gil-Gil, Joshua A Manuel, Andrew P Smith, Fernando Baquero, Bruce R Levin.
      The rational design of the antibiotic treatment of bacterial infections employs these drugs to reach concentrations that exceed the minimum needed to prevent the replication of the target bacteria. However, within a treated patient, spatial and physiological heterogeneity promotes antibiotic gradients such that the concentration of antibiotics at specific sites is below the minimum needed to inhibit bacterial growth. Here, we investigate the effects of sub-inhibitory antibiotic concentrations on three parameters central to bacterial infection and the success of antibiotic treatment, using in vitro experiments with Staphylococcus aureus and mathematical and computer-simulation models. Our results, using drugs of six different classes, demonstrate that exposure to sub-inhibitory antibiotic concentrations alters bacterial growth dynamics, increases the mutation rate to antibiotic resistance, and decreases the production of persister cells thereby reducing persistence levels. Understanding this trade-off between mutation rates and persistence levels resulting from sub-inhibitory antibiotic exposure is crucial for optimizing, and mitigating the failure of, antibiotic therapy.
    IMPORTANCE: Much of the research on antibiotics and antibiotic treatment has focused on drug concentrations sufficient to prevent the growth of bacteria. These concentrations, however, are not always reached everywhere in the body. Here, we look at the effects of exposure to these low concentrations of antibiotics on the common clinically important pathogen Staphylococcus aureus. We confirm a previous finding that sub-inhibitory antibiotic exposure decreases the total growth and the growth rate of the bacteria. Moreover, we demonstrate that the level of persistence, an important mechanism for bacteria to survive antibiotics, is decreased due to sub-inhibitory exposure. However, we find that the rate of generation of resistant mutants is substantially increased. Taken together, these results reveal an important trade-off that emerges as a consequence of bacteria being exposed to sub-inhibitory concentrations of antibiotics.
    Keywords:  Staphylococcus aureus; antibiotic heteroresistance; antibiotic resistance mutation rate; antibiotics; bacterial persistence; minimum inhibitory concentration; pharmacodynamics; population biology
    DOI:  https://doi.org/10.1128/spectrum.02479-24
  22. Microbiol Res. 2025 Feb 25. pii: S0944-5013(25)00078-3. [Epub ahead of print]296 128122
    Copper ions induces ferroptosis in Staphylococcus aureus and promotes healing of MRSA-induced wound infections.
    Lili Zhao, Hongbo Li, Zhenbin Liu, Zhen Wang, Dan Xu, Jiayi Zhang, Junjian Ran, Haizhen Mo, Liangbin Hu.
      The emergence of multidrug-resistant bacteria, particularly methicillin-resistant Staphylococcus aureus (MRSA), poses a significant threat to public health, necessitating new antimicrobial strategies. Here, we demonstrate that low doses of copper sulfate (CuSO4) exhibit potent bactericidal effects against both S. aureus and MRSA by inducing ferroptosis. CuSO4 treatment causes bacterial cell membrane perforation, increases intracellular free copper (Cu+) and ferrous ions (Fe2+), elevates reactive oxygen species (ROS) production and lipid peroxidation, and triggers the intracellular Fenton reaction. The use of ROS scavengers, copper chelators, iron chelators, and iron oxidase inhibitors attenuated ROS levels and lipid peroxidation, reducing Cu2+-mediated cell death, confirming the role of ferroptosis. Proteomic analysis revealed that Cu2+ enhances the expression of Fur protein, mediates iron release from intracellular stores, and inhibits glutathione biosynthesis. Furthermore, we developed a sodium alginate hydrogel loaded with CuSO4 (Cu-SA), which significantly improved wound healing and reduced inflammation and organ damage in an MRSA-infected mouse skin model. Our findings suggest that Cu2+-induced ferroptosis offers a promising alternative to traditional antibiotics for treating MRSA infections, providing a novel strategy to combat antibiotic resistance in S. aureus.
    Keywords:  Antimicrobial resistance; Copper ions; Cu-SA hydrogel; Ferroptosis; Staphylococcus aureus; Wound infection
    DOI:  https://doi.org/10.1016/j.micres.2025.128122
  23. Mater Today Bio. 2025 Apr;31 101571
    Functional hydrogels promote chronic infectious wound healing by re-rousing macrophage M1 and inducing bacterial copper-like death.
    Chao Xiang, Chaoyu Pu, XueMei Zhong, Yong Wang, Weiyong Song, Xingkuan Wang, Kemiao Chen, Kai Li, Yue Luo, Ke Jiang, Dianming Jiang.
      Traditional antibiotics are often ineffective against biofilm-associated infections, and biofilm-induced macrophage immune evasion directly halts the wound healing process. Disrupting biofilms and regulating macrophage immune functions are critical to improving wound healing. In this study, we synthesized g-C3N4 with peroxidase (POD) enzyme activity via thermal polymerization and copper alginate microspheres (CAM) via gas cutting. These were co-encapsulated into GelMA hydrogels to form a functionalized wound repair system (GelMA/CAM@g-C3N4) with both anti-biofilm and local immune microenvironment remodeling capabilities. In vitro, this system exhibited excellent biocompatibility and promoted endothelial cell migration, vascular formation, and CD31 expression. It also polarized macrophages toward the M1 phenotype, restoring their pro-inflammatory functions, upregulating inflammatory cytokines (IL-1, IL-6, TNF-α), and inhibiting Staphylococcus aureus and Escherichia coli. In vivo, the system suppressed S. aureus growth, promoted angiogenesis and collagen deposition, and reshaped the pathological microenvironment to achieve wound repair and regeneration. Conclusions: This system offers a new therapeutic strategy for chronic infectious wounds.
    Keywords:  Chronic infectious wounds; Hydrogels; Immune regulation; Macrophages; Microspheres
    DOI:  https://doi.org/10.1016/j.mtbio.2025.101571
  24. Arch Microbiol. 2025 Mar 04. 207(4): 76
    Akkermansia muciniphila: promises and pitfallsfor next-generation beneficial microorganisms.
    Yantong Liu, Zonglun Li, Sze Ching Lee, Shurui Chen, Feifei Li.
      Akkermansia muciniphila, a microorganism ubiquitously colonizing the mucosal layer of the human gut, has garnered significant scientific interest as a promising candidate for probiotic therapeutics. Its persistent identification in both laboratory and living organism studies underscores its potential physiological benefits, positioning it as a bacterium of paramount importance in promoting host health. This review examines the diversity and abundance of gut microbiota members, emphasizing the identification of microbial species engaged in cross-feeding networks with A. muciniphila. Insightful exploration into the mechanisms of cross-feeding, including mucin-derived nutrient exchange and metabolite production, unveils the intricate dynamics shaping microbial community stability. Such interactions contribute not only to the availability of essential nutrients within the gut environment but also to the production of metabolites influencing microbial community dynamics and host health. In conclusion, the cumulative evidence from in vitro and in vivo perspectives substantiates the notion that A. muciniphila holds tremendous promise as a next-generation probiotic. By leveraging its unique physiological benefits, particularly in mucosal health and metabolic regulation, A. muciniphila stands poised to revolutionize the landscape of probiotic interventions for enhanced host well-being.
    Keywords:   Akkermansia muciniphila ; Cross-feeding; Gut microbiota; Metabolic interaction; Probiotic
    DOI:  https://doi.org/10.1007/s00203-025-04263-w
  25. Annu Rev Immunol. 2025 Mar 04.
    The Interplay Between Innate Immunity and Nonimmune Cells in Lung Damage, Inflammation, and Repair.
    Chrysante S Iliakis, Stefania Crotta, Andreas Wack.
      As the site of gas exchange, the lung is critical for organismal survival. It is also subject to continual environmental insults inflicted by pathogens, particles, and toxins. Sometimes, these insults result in structural damage and the initiation of an innate immune response. Operating in parallel, the immune response aims to eliminate the threat, while the repair process ensures continual physiological function of the lung. The inflammatory response and repair processes are thus inextricably linked in time and space but are often studied in isolation. Here, we review the interplay of innate immune cells and nonimmune cells during lung insult and repair. We highlight how cellular cross talk can fine-tune the circuitry of the immune response, how innate immune cells can facilitate or antagonize proper organ repair, and the prolonged changes to lung immunity and physiology that can result from acute immune responses and repair processes.
    DOI:  https://doi.org/10.1146/annurev-immunol-082323-031852
  26. Open Biol. 2025 Mar;15(3): 240231
    Deciphering respiratory viral infections by harnessing organ-on-chip technology to explore the gut-lung axis.
    Hristina Koceva, Mona Amiratashani, Parastoo Akbarimoghaddam, Bianca Hoffmann, Gaukhar Zhurgenbayeva, Mark S Gresnigt, Vanessa Rossetto Marcelino, Christian Eggeling, Marc Thilo Figge, Maria-João Amorim, Alexander S Mosig.
      The lung microbiome has recently gained attention for potentially affecting respiratory viral infections, including influenza A virus, respiratory syncytial virus (RSV) and SARS-CoV-2. We will discuss the complexities of the lung microenvironment in the context of viral infections and the use of organ-on-chip (OoC) models in replicating the respiratory tract milieu to aid in understanding the role of temporary microbial colonization. Leveraging the innovative capabilities of OoC, particularly through integrating gut and lung models, opens new avenues to understand the mechanisms linking inter-organ crosstalk and respiratory infections. We will discuss technical aspects of OoC lung models, ranging from the selection of cell substrates for extracellular matrix mimicry, mechanical strain, breathing mechanisms and air-liquid interface to the integration of immune cells and use of microscopy tools for algorithm-based image analysis and systems biology to study viral infection in vitro. OoC offers exciting new options to study viral infections across host species and to investigate human cellular physiology at a personalized level. This review bridges the gap between complex biological phenomena and the technical prowess of OoC models, providing a comprehensive roadmap for researchers in the field.
    Keywords:  OoC; chips; lung; models; respiratory; viral
    DOI:  https://doi.org/10.1098/rsob.240231
  27. Med Mycol. 2025 Feb 28. pii: myaf018. [Epub ahead of print]63(3):
    Secreted factors of Aspergillus fumigatus cause lung epithelial barrier disruption: A study using an air-liquid interface cell culture model.
    Bianca Carla Silva Campitelli Barros, Debora Tereza Lucas Barros, Matthias Brock, Marcos Sergio Toledo, Solange Maria Toledo Serrano, Erika Suzuki, Amir M Ghaemmaghami.
      The effects of Aspergillus fumigatus-conditioned medium (AFCM) on the integrity of the Calu-3 cell lung epithelial barrier were investigated. AFCM led to a decrease in transepithelial electrical resistance and the disruption of the occludin network in the epithelial barrier. Preincubation with protease inhibitors reduced the effect of AFCM by ~ 90%, demonstrating the role of fungal proteases in epithelial barrier disruption. By mass spectrometry, we identified 494 unique proteins in AFCM, including 14 peptidases of different families. Together, these findings suggest that proteases secreted by A. fumigatus were able to modulate host epithelial barrier disruption in this fungal infection process.
    Keywords:   Aspergillus fumigatus ; air–liquid interface; disruption; epithelial barrier; protease
    DOI:  https://doi.org/10.1093/mmy/myaf018
  28. Immunol Cell Biol. 2025 Mar;103(3): 224-227
    Increased fatty acid production and macrophage-driven inflammation as key drivers of severe respiratory disease.
    Emily M Eriksson, Ivo Mueller.
      In this article, we discuss a recent article by Jia et al., where high OLAH expression was detected in severe and fatal respiratory disease which was associated with a number of processes and responses. These include high abundance of oleic acid, excessive cytokine release, high viral titres and lipid droplets and increased presence of lung-associated innate cells.
    Keywords:  fatty acid production; macrophage‐driven inflammation; severe respiratory disease
    DOI:  https://doi.org/10.1111/imcb.12852
  29. Front Immunol. 2025 ;16 1534009
    Acute hypoxia modulate macrophage phenotype accompanied with transcriptome re-programming and metabolic re-modeling.
    Binda Sun, Yao Long, Gang Xu, Jian Chen, Gang Wu, Bao Liu, Yuqi Gao.
       Introduction: Macrophages, which tend to aggregate in the hypoxic regions of tissues, have a significant impact on disease progression and outcome because of their plastic responsiveness to hypoxia, particularly in the early stages. Understanding macrophages'participation in hypoxia-related disorders requires demonstrating the impact of acute hypoxia on their survival, phenotype, and function.
    Methods: Here we conducted a systematic evaluation of macrophage responses to hypoxia over 24 and 48 h including cell growth and activity, inflamatory response, macrophage polarization and transcriptional and metabolic changes.
    Results: We found that acute hypoxia suppresses macrophage proliferation and phagocytosis function with a parallel change of transcriptome re-programming and metabolic re-modeling. Although macrophages accumulate transcriptome heterogeneity based on oxygen concentration and culture period, genes involved in hypoxia response, chemotaxis, and glycolytic process were commonly altered during acute hypoxia. Furthermore, the pro-inflammatory response of macrophages was activated during acute hypoxia concomitantly with an enhanced anti-inflammatory regulatory mechanism characterized by increased M2 macrophage population and anti-inflammatory metabolite itaconic acid. Aside from increased glycolysis, the key intermediates in the pentose phosphate pathway significantly increased, such as fructose 1,6-bisphosphate (fold change: 7.8), 6-phosphogluconate (fold change: 6.1), and ribose 5-phosphate (fold change: 3.9), which indicated that the pentose phosphate pathway was an important compensatory metabolic regulation that rules for the response of macrophages to acute hypoxia.
    Discussion: These findings highlight that acute hypoxia suppresses macrophage viability and phagocytosis, while acute hypoxia modifies the transcriptome and metabolome in specific inflammatory responses and metabolic pathways to facilitate the adaptation of macrophage in hypoxic conditions.
    Keywords:  acute hypoxia; macrophage; metabolic remodeling; pentose phosphate pathway; transcriptome reprogramming
    DOI:  https://doi.org/10.3389/fimmu.2025.1534009
  30. Sci Adv. 2025 Mar 07. 11(10): eadq1047
    TBK1 and IKKε prevent premature cell death by limiting the activity of both RIPK1 and NLRP3 death pathways.
    Fabian A Fischer, Benjamin Demarco, Felicia Chan Hui Min, Hui Wen Yeap, Dominic De Nardo, Kaiwen W Chen, Jelena S Bezbradica.
      The loss of TBK1, or both TBK1 and the related kinase IKKε, results in uncontrolled cell death-driven inflammation. Here, we show that the pathway leading to cell death depends on the nature of the activating signal. Previous models suggest that in steady state, TBK1/IKKε-deficient cells die slowly and spontaneously predominantly by uncontrolled tumor necrosis factor-RIPK1-driven death. However, upon infection of cells that express the NLRP3 inflammasome, (e.g., macrophages), with pathogens that activate this pathway (e.g., Listeria monocytogenes), TBK1/IKKε-deficient cells die rapidly, prematurely, and exclusively by enhanced NLRP3-driven pyroptosis. Even infection with the RIPK1-activating pathogen, Yersinia pseudotuberculosis, results in enhanced RIPK1-caspase-8 activation and enhanced secondary NLRP3 activation. Mechanistically, TBK1/IKKε control endosomal traffic, and their loss disrupts endosomal homeostasis, thereby signaling cell stress. This results in premature NLRP3 activation even upon sensing "signal 2" alone, without the obligatory "signal 1." Collectively, TBK1/IKKε emerge as a central brake in limiting death-induced inflammation by both RIPK1 and NLRP3 death-inducing pathways.
    DOI:  https://doi.org/10.1126/sciadv.adq1047
  31. Biochim Biophys Acta Mol Cell Res. 2025 Feb 27. pii: S0167-4889(25)00032-1. [Epub ahead of print]1872(4): 119927
    Lactylation and regulated cell death.
    Wenlong Zhang, Guangyao Shan, Guoshu Bi, Zhengyang Hu, Yanjun Yi, Dejun Zeng, Zongwu Lin, Cheng Zhan.
      Lactylation, a newly identified post-translational modification, entails the attachment of lactate to lysine residues within proteins, profoundly modulating diverse cellular mechanisms underlying regulated cell death (RCD). This modification encompasses two primary categories: histone lactylation and non-histone lactylation. Histone lactylation assumes a pivotal regulatory function in the RCD process, primarily by modulating the transcriptional landscape of genes implicated in cell death. In contrast, non-histone lactylation exerts its influence by targeting transferases, transcription, cell cycle progression, death pathways, and metabolic processes that are intricately involved in RCD. This review provides a comprehensive overview of recent breakthroughs in understanding how lactylation regulates RCD, while also offering insights into potential avenues for future research, thereby deepening our comprehension of cellular fate determination.
    Keywords:  Apoptosis; Autophagy; Ferroptosis; Lactylation; Pyroptosis
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.119927
  32. Clin Transl Immunology. 2025 ;14(3): e70026
    Decreased levels and function of dendritic cells in blood and airways predict COVID-19 severity.
    Björn Österberg, Sara Falck-Jones, Sindhu Vangeti, Eric Åhlberg, Meng Yu, Diana Granja, Marijn E Snik, Ryan Falck-Jones, Guilherme Wf Barros, Afandi Charles, Rico Lepzien, Niclas Johansson, Tyson H Holmes, Holden Maecker, Paulo Czarnewski, Max Bell, Anna Färnert, Anna Smed-Sörensen.
       Objectives: Monocytes and dendritic cells (DCs) are essential players in the immune response to infections, involved in shaping innate and adaptive immunity. However, a complete understanding of their specific roles in respiratory infections, including SARS-CoV-2, remains elusive.
    Methods: To investigate the dynamics of monocytes and DCs in blood as well as the upper and lower airways, we sampled 147 patients with varying degree of COVID-19 severity longitudinally during the spring of 2020.
    Results: Using flow cytometry, proteomics and in vitro TLR stimulation, we found differences in the distribution and function of monocytes and DCs in patients compared with controls, and importantly, reduced levels of DCs in both blood and airways. In fact, lower frequencies of cDC2s (Lin- HLA-DR+ CD1c+) early after symptom onset predicted subsequent severe disease, and depletion of DC subsets lasted longer in patients with more severe disease. In contrast, severe COVID-19 was associated with increased frequencies of activated monocytes in the lower, but not the upper, airways. Proteomic analysis showed that monocyte and DC-related cytokines in plasma and airways associated with disease severity. During convalescence, cell frequencies and responses to TLR ligands normalised in blood, except for persistently low plasmacytoid DCs.
    Conclusion: Our study reveals a distinct pattern of recruitment of monocytes but not DCs to the airways during severe COVID-19. Instead, decreased levels of DCs in both blood and airways were found, possibly contributing to more severe COVID-19. The connection between low blood DCs early in disease course and more severe outcomes provides insight into COVID-19 immunopathology, with possible therapeutic implications.
    Keywords:  COVID‐19; SARS‐CoV‐2; dendritic cells; monocytes; respiratory immunology
    DOI:  https://doi.org/10.1002/cti2.70026
  33. Clin Microbiol Infect. 2025 Feb 26. pii: S1198-743X(25)00082-5. [Epub ahead of print]
    Evaluating infection risk associated with Staphylococcus aureus nasal carriage in blood donors: a prospective multicentre study in Denmark.
    Khoa Manh Dinh, Kathrine Agergård Kaspersen, Jens Kjærgaard Boldsen, Svend Ellermann-Eriksen, Sisse Rye Ostrowski, Bitten Aagaard, Henrik Hjalgrim, Ole Birger Pedersen, Lise Tornvig Erikstrup, Christian Erikstrup.
       OBJECTIVE: To investigate whether Staphylococcus aureus nasal carriage influences susceptibility to community-acquired S. aureus-associated infection and any other bacterial infection risk in healthy individuals.
    METHODS: This prospective cohort study included blood donors aged 18-70 years between 2014-2021 in Denmark. A nasal swab cultivated for S. aureus defined carriage type (exposure) and infection endpoints were redeemed antibacterial prescriptions or ICD-10 diagnoses from national registers. Adjusted incidence rate ratio (IRR) was estimated using Poisson regression for prescriptions while Cox regression estimated hazard ratio for diagnoses.
    RESULTS: Of 8,738 included participants, 3,503 (40.5%) were carriers. During a median follow-up of 3.8 years (IQR: 2.4-5.1), 1,110 participants redeemed dicloxacillin/flucloxacillin and 1,412 redeemed topical fusidic acid prescriptions while 378 participants received hospital treatment for infections during 3.4 years (IQR: 1.9-4.6). Nasal carriers redeemed dicloxacillin and topical fusidic acid prescriptions more often than non-carriers (IRR 1.40 [95% CI: 1.24-1.58] and IRR 1.22 [1.10-1.36], respectively). Participants who redeemed one dicloxacillin prescription were six times more likely to redeem another within two years. Among these, carriers had a higher incidence of redeeming additional dicloxacillin prescriptions than non-carriers (absolute risk, 19.0% vs 12.9%, respectively; IRR 1.46 [1.17-1.84]). S. aureus nasal carriage was not associated with higher risk of redeeming other antibacterial prescriptions nor with risk of hospital-treated S. aureus and any other bacterial infections.
    CONCLUSION: In this study comprising healthy adults, nasal carriers with S. aureus exhibited an increased risk of redeemed dicloxacillin and topical fusidic acid prescriptions, but nasal carriage was not associated with any other types of bacterial infection. Findings suggest that nasal carriage elevates the burden of community-acquired S. aureus infections.
    Keywords:  Community-acquired infections; Donor health; Infection risk; Nasal colonisation; Staphylococcus aureus
    DOI:  https://doi.org/10.1016/j.cmi.2025.02.021
  34. Cytometry A. 2025 Mar 07.
    Cytometry at the Intersection of Metabolism and Epigenetics in Lymphocyte Dynamics.
    Nicole Vaughn.
      Landmark studies at the turn of the century revealed metabolic reprogramming as a driving force for lymphocyte differentiation and function. In addition to metabolic changes, differentiating lymphocytes must remodel their epigenetic landscape to properly rewire their gene expression. Recent discoveries have shown that metabolic shifts can shape the fate of lymphocytes by altering their epigenetic state, bringing together these two areas of inquiry. The ongoing evolution of high-dimensional cytometry has enabled increasingly comprehensive analyses of metabolic and epigenetic landscapes in lymphocytes that transcend the technical limitations of the past. Here, we review recent insights into the interplay between metabolism and epigenetics in lymphocytes and how its dysregulation can lead to immunological dysfunction and disease. We also discuss the latest technical advances in cytometry that have enabled these discoveries and that we anticipate will advance future work in this area.
    DOI:  https://doi.org/10.1002/cyto.a.24919
  35. Front Immunol. 2025 ;16 1488699
    Applying 3D cultures and high-throughput technologies to study host-pathogen interactions.
    Elaine Cristina Pereira De Martinis, Virgínia Farias Alves, Marita Gimenez Pereira, Leonardo Neves Andrade, Nathália Abichabki, Anna Abramova, Mirjam Dannborg, Johan Bengtsson-Palme.
      Recent advances in cell culturing and DNA sequencing have dramatically altered the field of human microbiome research. Three-dimensional (3D) cell culture is an important tool in cell biology, in cancer research, and for studying host-microbe interactions, as it mimics the in vivo characteristics of the host environment in an in vitro system, providing reliable and reproducible models. This work provides an overview of the main 3D culture techniques applied to study interactions between host cells and pathogenic microorganisms, how these systems can be integrated with high-throughput molecular methods, and how multi-species model systems may pave the way forward to pinpoint interactions among host, beneficial microbes and pathogens.
    Keywords:  high-throughput sequencing; microbial model communities; organ-on-a-chip; organoids; rotating wall vessel (RWV); transposon sequencing (TnSeq); tridimensional cell culture
    DOI:  https://doi.org/10.3389/fimmu.2025.1488699
  36. Microbiome. 2025 Mar 04. 13(1): 65
    Absolute quantification of the living skin microbiome overcomes relic-DNA bias and reveals specific patterns across volunteers.
    Deepan Thiruppathy, Oriane Moyne, Clarisse Marotz, Michael Williams, Perris Navarro, Livia Zaramela, Karsten Zengler.
       BACKGROUND: As the first line of defense against external pathogens, the skin and its resident microbiota are responsible for protection and eubiosis. Innovations in DNA sequencing have significantly increased our knowledge of the skin microbiome. However, current characterizations do not discriminate between DNA from live cells and remnant DNA from dead organisms (relic DNA), resulting in a combined readout of all microorganisms that were and are currently present on the skin rather than the actual living population of the microbiome. Additionally, most methods lack the capability for absolute quantification of the microbial load on the skin, complicating the extrapolation of clinically relevant information.
    RESULTS: Here, we integrated relic-DNA depletion with shotgun metagenomics and bacterial load determination to quantify live bacterial cell abundances across different skin sites. Though we discovered up to 90% of microbial DNA from the skin to be relic DNA, we saw no significant effect of this on the relative abundances of taxa determined by shotgun sequencing. Relic-DNA depletion prior to sequencing strengthened underlying patterns between microbiomes across volunteers and reduced intraindividual similarity. We determined the absolute abundance and the fraction of population alive for several common skin taxa across body sites and found taxa-specific differential abundance of live bacteria across regions to be different from estimates generated by total DNA (live + dead) sequencing.
    CONCLUSIONS: Our results reveal the significant bias relic DNA has on the quantification of low biomass samples like the skin. The reduced intraindividual similarity across samples following relic-DNA depletion highlights the bias introduced by traditional (total DNA) sequencing in diversity comparisons across samples. The divergent levels of cell viability measured across different skin sites, along with the inconsistencies in taxa differential abundance determined by total vs live cell DNA sequencing, suggest an important hypothesis for certain sites being susceptible to pathogen infection. Overall, our study demonstrates a characterization of the skin microbiome that overcomes relic-DNA bias to provide a baseline for live microbiota that will further improve mechanistic studies of infection, disease progression, and the design of therapies for the skin. Video Abstract.
    Keywords:  Absolute abundance; Flow cytometry; Metagenomics; Relic DNA; Skin microbiome
    DOI:  https://doi.org/10.1186/s40168-025-02063-4
  37. J Infect Dis. 2025 Mar 03. pii: jiaf099. [Epub ahead of print]
    Clinical isolates of antimicrobial resistant Enterobacter species can persist in human macrophages without replication and overt cellular cytotoxicity.
    Georgiana Parau, Hannah J Parks, Amy J G Anderson, Fabiana Bisaro, Inmaculada García-Romero, Michael C Gilmore, Samuel O Korankye, Helina Marshall, Miguel A Valvano.
       BACKGROUND: Enterobacter species are opportunistic, multidrug resistant Gram-negative bacteria associated with morbidity and mortality worldwide. Since very little is known about the infection biology of Enterobacter spp., we investigated the intracellular trafficking of a subset of Enterobacter clinical isolates, including colistin-resistant strains, within human macrophages, and determined the macrophage response to the intracellular infection.
    METHODS: Phagocytosis of 11 clinical isolates representing E. cloacae, E. bugandensis, E. kobei, E. xiangfangensis, E. roggenkampii, E. hoffmannii, and E. ludwigii was investigated in primary human macrophages. Intracellular bacterial trafficking was followed by confocal fluorescence microscopy; intracellular bacterial replication was assessed by bacterial enumeration and a fluorescence dilution approach to follow bacterial cell division over time. Macrophage cell cytotoxicity was investigated by quantifying the release of lactate dehydrogenase during infection and by determining cleavage of the proinflammatory markers caspase-1, gasdermin D and pro-interleukin-1β.
    RESULTS: Enterobacter isolates did not replicate in human macrophages, exhibiting long-term survival (up to 44 hours) within a modified late phagolysosome compartment. Survival did not correlate with colistin resistance, lipopolysaccharide modifications, or bacterial pathogenicity in the Galleria mellonella infection model. Intracellular bacteria induce low levels of macrophage cytotoxicity that correlated with absence of cleavage of proinflammatory markers in infected macrophages.
    CONCLUSIONS: Enterobacter spp clinical isolates can persist without replication inside human macrophages with minimal effects on cell viability and inflammation. These observations could have implications in the clinical outcome of patients that cannot readily clear Enterobacter infections, which can potentially lead to prolonged intracellular survival and infection relapse.
    DOI:  https://doi.org/10.1093/infdis/jiaf099
  38. Microbiome. 2025 Feb 28. 13(1): 58
    An in vitro model demonstrating homeostatic interactions between reconstructed human gingiva and a saliva-derived multispecies biofilm.
    Lin Shang, Sanne Roffel, Vera Slomka, Eleanor M D'Agostino, Aline Metris, Mark J Buijs, Bernd W Brandt, Dongmei Deng, Susan Gibbs, Bastiaan P Krom.
       BACKGROUND: In the oral cavity, host-microbe interactions (HMI) continuously occur and greatly impact oral health. In contrast to the well-studied disease-associated HMI during, for example, periodontitis, HMI that are essential in maintaining oral health have been rarely investigated, especially in a human-relevant context. The aim of this study was to extensively characterize homeostatic HMI between saliva-derived biofilms and a reconstructed human gingiva (RHG). RHG was reconstructed following the structure of native gingiva, composed of a multilayered epithelium formed by keratinocytes and a fibroblast-populated compartment. To mimic the oral environment, RHG were inoculated with pooled human saliva resuspended in different saliva substitute media and incubated for 2 or 4 days. The co-cultured biofilms were retrieved and characterized by viable bacterial counting and compositional profiling (16S rRNA gene sequencing). RHG was investigated for metabolic activity (MTT assay), tissue histology (hematoxylin and eosin staining), epithelial proliferation (Ki67 staining), antimicrobial peptide expression, and cytokine secretion.
    RESULTS: Viable biofilms were detected up to day 4 of co-culturing. Bacterial counts indicated biofilm growth from the inoculation to day 2 and maintained thereafter at a similar level until day 4. All biofilms shared similar composition throughout 4 days, independent of co-culture time and different saliva substitute media used during inoculation. Biofilms were diverse with Streptococcus, Haemophilus, and Neisseria being the dominating genera. While supporting biofilm development, RHG displayed no significant changes in metabolic activity, tissue histology, or epithelial proliferation. However, in the presence of biofilms, the antimicrobial peptides elafin and human β-defensin-2 were upregulated, and the secretion of cytokines IL-6, CXCL1, CXCL8, CCL5, and CCL20 increased.
    CONCLUSION: This model mimicked homeostatic HMI where a healthy gingiva supported a viable, diverse, and stable microbial community, incorporating bacterial genera found on native gingiva. The gingiva model maintained its tissue integrity and exerted protective responses in the presence of biofilms over time. This study adds to the evidence that shows the important role of the host in maintaining homeostatic HMI that are essential for oral health. Video Abstract.
    Keywords:  16S rRNA gene sequencing; Biofilms; Gingiva; Host-microbe interactions; Organotypic model
    DOI:  https://doi.org/10.1186/s40168-025-02033-w
  39. NPJ Biofilms Microbiomes. 2025 Mar 04. 11(1): 38
    Molecules-mediated bidirectional interactions between microbes and human cells.
    Shengbo Wu, Xueying Bu, Danlei Chen, Xueyan Wu, Hao Wu, Qinggele Caiyin, Jianjun Qiao.
      Complex molecules-mediated interactions, which are based on the bidirectional information exchange between microbes and human cells, enable the defense against diseases and health maintenance. Recently, diverse single-direction interactions based on active metabolites, immunity factors, and quorum sensing signals have largely been summarized separately. In this review, according to a simplified timeline, we proposed the framework of Molecules-mediated Bidirectional Interactions (MBI) between microbe and humans to decipher and understand their intricate interactions systematically. About the microbe-derived interactions, we summarized various molecules, such as short-chain fatty acids, bile acids, tryptophan catabolites, and quorum sensing molecules, and their corresponding human receptors. Concerning the human-derived interactions, we reviewed the effect of human molecules, including hormones, cytokines, and other circulatory metabolites on microbial characteristics and phenotypes. Finally, we discussed the challenges and trends for developing and deciphering molecule-mediated bidirectional interactions and their potential applications in the guard of human health.
    DOI:  https://doi.org/10.1038/s41522-025-00657-2
  40. FEBS J. 2025 Mar 06.
    TAK1 at the crossroads of multiple regulated cell death pathways: from molecular mechanisms to human diseases.
    Kun Huang, Qi Zhang, Hao Wan, Xiao-Xia Ban, Xin-Yu Chen, Xin-Xing Wan, Rui Lu, Ye He, Kun Xiong.
      Regulated cell death (RCD), the form of cell death that can be genetically controlled by multiple signaling pathways, plays an important role in organogenesis, tissue remodeling, and maintenance of organism homeostasis and is closely associated with various human diseases. Transforming growth factor-beta-activated kinase 1 (TAK1) is a member of the serine/threonine protein kinase family, which can respond to different internal and external stimuli and participate in inflammatory and immune responses. Emerging evidence suggests that TAK1 is an important regulator at the crossroad of multiple RCD pathways, including apoptosis, necroptosis, pyroptosis, and PANoptosis. The regulation of TAK1 affects disease progression through multiple signaling pathways, and therapeutic strategies targeting TAK1 have been proposed for inflammatory diseases, central nervous system diseases, and cancers. In this review, we provide an overview of the downstream signaling pathways regulated by TAK1 and its binding proteins. Their critical regulatory roles in different forms of cell death are also summarized. In addition, we discuss the potential of targeting TAK1 in the treatment of human diseases, with a specific focus on neurological disorders and cancer.
    Keywords:  PANoptosis; TAK1; apoptosis; necroptosis; neurological disorder; regulated cell death
    DOI:  https://doi.org/10.1111/febs.70042
  41. Nature. 2025 Mar 05.
    Cell-autonomous innate immunity by proteasome-derived defence peptides.
    Karin Goldberg, Arseniy Lobov, Paola Antonello, Merav D Shmueli, Idan Yakir, Tal Weizman, Adi Ulman, Daoud Sheban, Einav Laser, Matthias P Kramer, Ronen Shteinvil, Guoyun Chen, Angham Ibraheem, Vera Sysoeva, Vered Fishbain-Yoskovitz, Gayatree Mohapatra, Anat Abramov, Sandy Shimshi, Kseniia Ogneva, Madhurima Nandy, Sivan Amidror, Hadar Bootz-Maoz, Shanny H Kuo, Nili Dezorella, Assaf Kacen, Aaron Javitt, Gee W Lau, Nissan Yissachar, Zvi Hayouka, Yifat Merbl.
      For decades, antigen presentation on major histocompatibility complex class I for T cell-mediated immunity has been considered the primary function of proteasome-derived peptides1,2. However, whether the products of proteasomal degradation play additional parts in mounting immune responses remains unknown. Antimicrobial peptides serve as a first line of defence against invading pathogens before the adaptive immune system responds. Although the protective function of antimicrobial peptides across numerous tissues is well established, the cellular mechanisms underlying their generation are not fully understood. Here we uncover a role for proteasomes in the constitutive and bacterial-induced generation of defence peptides that impede bacterial growth both in vitro and in vivo by disrupting bacterial membranes. In silico prediction of proteome-wide proteasomal cleavage identified hundreds of thousands of potential proteasome-derived defence peptides with cationic properties that may be generated en route to degradation to act as a first line of defence. Furthermore, bacterial infection induces changes in proteasome composition and function, including PSME3 recruitment and increased tryptic-like cleavage, enhancing antimicrobial activity. Beyond providing mechanistic insights into the role of proteasomes in cell-autonomous innate immunity, our study suggests that proteasome-cleaved peptides may have previously overlooked functions downstream of degradation. From a translational standpoint, identifying proteasome-derived defence peptides could provide an untapped source of natural antibiotics for biotechnological applications and therapeutic interventions in infectious diseases and immunocompromised conditions.
    DOI:  https://doi.org/10.1038/s41586-025-08615-w
  42. Bioact Mater. 2025 May;47 417-431
    LA-peptide Hydrogel-Regulation of macrophage and fibroblast fates and their crosstalk via attenuating TGF-β to promote scarless wound healing.
    Zichao Li, Leyang Zhang, Yang Wang, Yifu Zhu, Haomiao Shen, Juzheng Yuan, Xiao Li, Zhou Yu, Baoqiang Song.
      The homeostasis of the wound microenvironment is fundamental for scarless wound healing, while the excessive accumulation of transforming growth factor-beta (TGF-β) in the wound microenvironment always leads to hypertrophic scars (HS) formation by regulating cell fates and crosstalk among various types of cells, such as macrophages and fibroblasts. This study reports that an injectable, self-assembling LA-peptide hydrogel has the potential to facilitate scarless cutaneous wound healing through dynamically adsorbing TGF-β within the wound environment. We found that the released LA peptides led to the suppression of both the PI3K/Akt and TGF-β/Smad2/3 pathways in macrophages and fibroblasts. As expected, the application of LA-peptide hydrogel alleviated the M2 type polarization of macrophages and inhibited fibroblasts activation by adsorbing TGF-β both in vitro and in vivo. Furthermore, designated concentrations of the LA-peptide hydrogel achieved controlled release of LA peptides, enabling dynamic regulation of TGF-β for maintaining microenvironment homeostasis during different phases of wound healing. This contributed to the inhibition of HS formation without delaying wound healing in both a mouse full-thickness skin wound model and a rabbit ear scar model. Overall, the LA-peptide hydrogel provides promising avenues for promoting scarless healing of wounds, exemplifying precision medicine-guided targeting of specific pathogenic molecules, such as TGF-β, and highlighting the significance of dynamic regulation of TGF-β homeostasis in wound microenvironment.
    Keywords:  Fibroblast activation; LA-Peptide hydrogel; Macrophage M2 type polarization; TGF-β signaling; Wound microenvironment
    DOI:  https://doi.org/10.1016/j.bioactmat.2025.02.005
  43. Front Immunol. 2025 ;16 1529756
    Epigenetic regulation of transcription factors involved in NLRP3 inflammasome and NF-kB signaling pathways.
    John Kaszycki, Minji Kim.
      The NLRP3 inflammasome and NF-κB signaling pathways play crucial roles in orchestrating inflammation and immune defense.​ This review explores the intricate relationship between these pathways and epigenetic regulation, a field of growing importance in understanding immune responses. Epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNAs (ncRNAs), significantly influence the activity of genes involved in these pathways, thereby modulating inflammatory responses. The review provides a comprehensive overview of current research on how epigenetic mechanisms interact with and regulate the NLRP3 inflammasome and NF-κB signaling pathways. It delves into advanced epigenetic concepts such as RNA modifications and 3D genome organization, and their impact on immune regulation. Furthermore, the implications of these findings for developing novel therapeutic strategies targeting epigenetic regulators in inflammatory diseases are discussed. By synthesizing recent advancements in this rapidly evolving field, this review underscores the critical role of epigenetic regulation in immune signaling and highlights the potential for epigenetic-based therapies in treating a wide range of inflammatory conditions, including autoimmune disorders and cancer.
    Keywords:  NF-κB signaling; NLRP3 inflammasome; chromatin remodeling; epigenetics; inflammation
    DOI:  https://doi.org/10.3389/fimmu.2025.1529756
  44. Nat Cancer. 2025 Mar 04.
    An antibody-toxin conjugate enhances innate immune cell responses in tumors.
      
    DOI:  https://doi.org/10.1038/s43018-025-00920-7
  45. mBio. 2025 Mar 05. e0388324
    Spontaneous lung colonization in the cystic fibrosis rat model is linked to gastrointestinal obstruction.
    Mikayla Murphree-Terry, Johnathan D Keith, Ashley M Oden, Susan E Birket.
      Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in CFTR protein dysfunction. CFTR dysfunction has multi-organ consequences, leading to dehydrated mucus that is adherent to epithelia. In the lungs, this leads to recalcitrant infections with bacteria such as Pseudomonas aeruginosa. In the gut, mucus-laden feces can adhere to the intestines, resulting in distal intestinal obstruction syndrome (DIOS). There is limited information on how lung colonization and DIOS are correlated in people with CF (pwCF). In this novel work, we describe the development of spontaneous lung colonization of CF pathogens in young (<3 months old) CF rats, preceding the development of DIOS. Once DIOS is established, the lung microbiome becomes predominated by taxa also observed in the feces. Induced infection with P. aeruginosa in the CF rats reflects data found in pwCF, as once CF rats are infected, they retain a higher relative abundance of P. aeruginosa than their healthy agemates. Finally, we found that ivacaftor treatment favors a healthier gut microbiome in CF rats, decreasing the relative abundance of Escherichia coli. These results indicate that the CF rat model is recapitulative of human CF disease with the spontaneous lung colonization of traditional CF pathogens and maintenance of P. aeruginosa after induced infection. Furthermore, these results indicate a possible role for the gut-lung axis in lung colonization and DIOS in CF.IMPORTANCEThese data describe for the first time the development of spontaneous lung colonization in the cystic fibrosis (CF) rat model, a hallmark aspect of human CF disease. We also find that CF rats infected with Pseudomonas aeruginosa maintain higher relative abundance following chronic infection as compared to healthy rats, similar to those is seen in people with CF. Additionally, we describe the possible contribution of the gut-lung axis linking lung health with distal intestinal obstruction syndrome, a relationship largely unexplored in the context of CF.
    Keywords:  DIOS; airway colonization; cystic fibrosis; microbiome; mucus
    DOI:  https://doi.org/10.1128/mbio.03883-24
  46. Front Immunol. 2025 ;16 1475480
    Single-cell analysis of CD14+CD16+ monocytes identifies a subpopulation with an enhanced migratory and inflammatory phenotype.
    Vanessa Y Ruiz, Tina M Calderon, Rosiris Leon-Rivera, Vanessa Chilunda, Jinghang Zhang, Joan W Berman.
      Monocytes in the central nervous system (CNS) play a pivotal role in surveillance and homeostasis, and can exacerbate pathogenic processes during injury, infection, or inflammation. CD14+CD16+ monocytes exhibit diverse functions and contribute to neuroinflammatory diseases, including HIV-associated neurocognitive impairment (HIV-NCI). Analysis of human CD14+CD16+ monocytes matured in vitro by single-cell RNA sequencing identified a heterogenous population of nine clusters. Ingenuity pathway analysis of differentially expressed genes in each cluster identified increased migratory and inflammatory pathways for a group of clusters, which we termed Group 1 monocytes. Group 1 monocytes, distinguished by increased ALCAM, CD52, CD63, and SDC2, exhibited gene expression signatures implicated in CNS inflammatory diseases, produced higher levels of CXCL12, IL-1Ra, IL-6, IL-10, TNFα, and ROS, and preferentially transmigrated across a human in vitro blood-brain barrier model. Thus, Group 1 cells within the CD14+CD16+ monocyte subset are likely to be major contributors to neuroinflammatory diseases.
    Keywords:  BBB; CD14+CD16+ monocytes; ROS; cytokines; intermediate monocytes; scRNA-seq
    DOI:  https://doi.org/10.3389/fimmu.2025.1475480
  47. Int J Antimicrob Agents. 2025 Feb 28. pii: S0924-8579(25)00036-6. [Epub ahead of print] 107479
    Cross-Talk Between Signal Transduction Systems and Metabolic Networks in Bacterial Antibiotics Resistance and Tolerance.
    Shuji Gao, Baobao Liu, Shuo Yuan, Yingying Quan, Shenao Song, Wenjie Jin, Yuxin Wang, Yang Wang.
      The comprehensive antibiotic resistance of pathogens signifies the oneset of the "post-antibiotic era", and the myriad treatment challenges posed by "superbugs" have emerged as the primary threat to human health. Recent studies indicate that bacterial resistance and tolerance development are mediated at the metabolic level by various signaling networks (e.g., quorum sensing systems, second messenger systems, and two-component systems), resulting in metabolic rearrangements and alterations in bacterial community behavior. This review focuses on current research, highlighting the intrinsic link between signaling and metabolic networks in bacterial resistance and tolerance.
    Keywords:  Metabolism; Resistance; Signaling; Tolerance
    DOI:  https://doi.org/10.1016/j.ijantimicag.2025.107479
  48. Endocrinology. 2025 Feb 27. pii: bqaf004. [Epub ahead of print]166(4):
    Gut Microbiome Regulation of Gut Hormone Secretion.
    Jessica Chao, Rosemary A Coleman, Damien J Keating, Alyce M Martin.
      The gut microbiome, comprising bacteria, viruses, fungi, and bacteriophages, is one of the largest microbial ecosystems in the human body and plays a crucial role in various physiological processes. This review explores the interaction between the gut microbiome and enteroendocrine cells (EECs), specialized hormone-secreting cells within the intestinal epithelium. EECs, which constitute less than 1% of intestinal epithelial cells, are key regulators of gut-brain communication, energy metabolism, gut motility, and satiety. Recent evidence shows that gut microbiota directly influence EEC function, maturation, and hormone secretion. For instance, commensal bacteria regulate the production of hormones like glucagon-like peptide 1 and peptide YY by modulating gene expression and vesicle cycling in EE cells. Additionally, metabolites such as short-chain fatty acids, derived from microbial fermentation, play a central role in regulating EEC signaling pathways that affect metabolism, gut motility, and immune responses. Furthermore, the interplay between gut microbiota, EECs, and metabolic diseases, such as obesity and diabetes, is examined, emphasizing the microbiome's dual role in promoting health and contributing to disease states. This intricate relationship between the gut microbiome and EECs offers new insights into potential therapeutic strategies for metabolic and gut disorders.
    Keywords:  enteroendocrine cells; gut hormone; gut microbiome; host physiology
    DOI:  https://doi.org/10.1210/endocr/bqaf004
  49. Front Immunol. 2025 ;16 1516120
    Caspase-11 and NLRP3 exacerbate systemic Klebsiella infection through reducing mitochondrial ROS production.
    Yuqi Zhou, Zhuodong Chai, Ankit Pandeya, Ling Yang, Yan Zhang, Guoying Zhang, Congqing Wu, Zhenyu Li, Yinan Wei.
       Introduction: Klebsiella pneumoniae is a Gram-negative bacterium and the third most commonly isolated microorganism in blood cultures from septic patients. Despite extensive research, the mechanisms underlying K. pneumoniae-induced sepsis and its pathogenesis remain unclear. Acute respiratory failure is a leading cause of mortality in systemic K. pneumoniae infections, highlighting the need to better understand the host immune response and bacterial clearance mechanisms.
    Method: To investigate the impact of K. pneumoniae infection on organ function and immune response, we utilized a systemic infection model through intraperitoneal injection in mice. Bacterial loads in key organs were quantified, and lung injury was assessed. Survival analysis was performed in wild-type (WT) and gene deficient mice. Mitochondrial damage and reactive oxygen species (ROS) production, as well as cytokine levels were measured in macrophages isolated from these mice to evaluate their contribution to bacterial clearance capacity.
    Results: Our findings demonstrate that K. pneumoniae systemic infection results in severe lung injury and significant bacterial accumulation in multiple organs, with the highest burden in the lungs. Deficiency of caspase-11 or NLRP3 led to prolonged survival, a reduction in pulmonary bacterial load, increased blood oxygen levels, and decreased IL-6 levels in the lungs compared to WT controls. Furthermore, caspase-11- and NLRP3-deficient macrophages exhibited elevated mitochondrial ROS production in response to K. pneumoniae, which correlated with more effective bacterial clearance.
    Discussion: These results suggest that caspase-11 and NLRP3 contribute to K. pneumoniae-induced sepsis by impairing mitochondrial function and reducing ROS production in macrophages, thereby compromising bacterial clearance. The observed reduction in lung injury and increased survival in caspase-11- and NLRP3-deficient mice indicate that targeting these pathways may offer potential therapeutic strategies to improve host defense against systemic K. pneumoniae infection.
    Keywords:  Klebsiella; NLRP3; ROS; caspase-11; inflammasome; pneumonia; sepsis
    DOI:  https://doi.org/10.3389/fimmu.2025.1516120
This page is being maintained by Thomas Krichel. It was last updated on 2025‒03‒23 at 5:20.