bims-bac4me Biomed News
on Microbiome and trained immunity
Issue of 2025–05–11
twenty-one papers selected by
Chun-Chi Chang, Universitäts Spital Zürich



  1. Cell. 2025 Apr 25. pii: S0092-8674(25)00400-3. [Epub ahead of print]
      Trained immunity, a de facto innate immune memory characterized by enhanced responsiveness to future challenges, is underpinned by epigenetic and metabolic rewiring. In individuals vaccinated with Bacille Calmette-Guérin (BCG), lactate release was associated with enhanced cytokine responsiveness upon restimulation. Trained monocytes/macrophages are characterized by lactylation of histone H3 at lysine residue 18(H3K18la), mainly at distal regulatory regions. Histone lactylation was positively associated with active chromatin and gene transcription, persisted after the elimination of the training stimulus, and was strongly associated with "trained" gene transcription in response to a secondary stimulus. Increased lactate production upon induction of trained immunity led to enhanced production of proinflammatory cytokines, a process associated with histone lactylation. Pharmacological inhibition of lactate production or histone lactylation blocked trained immunity responses, while polymorphisms of LDHA and EP300 genes modulated trained immunity. Long-term histone lactylation persisted in vivo 90 days after vaccination with BCG, highlighting H3K18la as an epigenetic mark of innate immune memory.
    Keywords:  BCG; Bacillus Calmette-Guérin; H3K18la; lactate; lactylation; trained immunity
    DOI:  https://doi.org/10.1016/j.cell.2025.03.048
  2. PLoS One. 2025 ;20(5): e0321462
       OBJECTIVE: The airway epithelium provides a first line of defense against pathogens by release of antimicrobial factors and neutrophil-attracting chemokines. Pseudomonas (P.) aeruginosa, a Gram-negative bacterium that expresses flagellin as an important virulence factor, is a common cause of injurious airway inflammation. The aim of our study was to determine the contribution of flagellin to the inflammatory, antimicrobial, and metabolic responses of the airway epithelium to P. aeruginosa. Furthermore, as we previously showed that targeting mTOR limited the glycolytic and inflammatory response induced by flagellin, we assessed the effect of rapamycin on human bronchial epithelial (HBE) cells stimulated with flagellated and non-flagellated P. aeruginosa.
    METHODS: Primary pseudostratified HBE cells, cultured on an air-liquid-interface, were treated on the basolateral side with medium, vehicle or rapamycin, exposed on the apical side with flagellated or flagellin-deficient P. aeruginosa, and analyzed for their inflammatory, antimicrobial, and glycolytic responses.
    RESULTS: Flagellin augmented the P. aeruginosa-induced expression of antimicrobial factors and secretion of chemokines by HBE cells but did not further increase the glycolytic response. Treatment of HBE cells with rapamycin inhibited mTOR activation in general and flagellin-augmented mTOR activation in particular, but did not affect the glycolytic response. Rapamycin, however, diminished the flagellin-augmented inflammatory and antimicrobial response induced by Pseudomonas.
    CONCLUSIONS: These results demonstrate that flagellin is a significant factor that augments the inflammatory and antimicrobial response of human airway epithelial cells upon exposure to P. aeruginosa and suggest that mTOR inhibition by rapamycin in the airway epithelium diminishes these exaggerated responses.
    DOI:  https://doi.org/10.1371/journal.pone.0321462
  3. Int Immunopharmacol. 2025 May 07. pii: S1567-5769(25)00787-8. [Epub ahead of print]157 114797
      Macrophages are the first line of defense in the innate immune system. Macrophages have two subtypes: classically activated macrophages (M1) and alternatively activated macrophages (M2), with different phenotypes and functions. They play a critical role in defending against pathogens and maintaining internal homeostasis. Macrophages have great plasticity in their biological characteristics. Although the regulation of macrophage plasticity has not been fully elucidated, accumulated evidence supports that microenvironmental differences are the root cause for macrophage differentiation into different subtypes. These differences alter macrophage plasticity by modulating key metabolites, activating downstream gene transcription, and influencing phagocytosis, cytokine secretion, and immune regulation. Herein, we systematically summarize metabolic reprogramming, including glucose, lipid, amino acid, ion, vitamin, nucleotide, and butyrate metabolism, as key regulators affecting macrophage polarization, providing new insights for developing targeted drugs that modulate macrophage plasticity.
    Keywords:  Amino acid metabolism; Glycolipid metabolism; Ion metabolism; Macrophage plasticity; Metabolic reprogramming; Vitamin metabolism
    DOI:  https://doi.org/10.1016/j.intimp.2025.114797
  4. FASEB J. 2025 May 15. 39(9): e70536
      PTPN2 is encoded by the protein tyrosine phosphatase N2 (also known as TC-PTP) and is a negative regulator of cytokine signaling and macrophage differentiation. In the past decade, our work and others, including several pharmaceuticals, have emphasized that inhibition of PTPN2 and PTPN1 (also known as PTP1B) may act as a new first-of-class cancer immunotherapeutic. Although the potential roles of these two enzymes in various immune cells have been broadly reported, the specific activity of PTPN2 in regulating macrophage immune and metabolic responses has yet to be fully elucidated. Hence, we sought to investigate the function of PTPN2 in macrophage polarization and on their activities. We used two different mouse models to systematically and specifically inhibit the expression of PTPN2 in macrophages and utilized a chemical inhibitor with a macrophage human cell line to assess their immune and metabolic profiles. We demonstrated that PTPN2 ablation in macrophages alters their immunometabolic transcriptome and enhances their proinflammatory response, as observed by increased IFN-ɣ and nitric oxide production. PTPN2 deficiency also leads to a dysregulation of mitochondrial respiration, as observed by decreased oxygen consumption and ATP production. We establish herein that PTPN2 dampens the proinflammatory response of macrophages while altering their mitochondrial respiration, validating its macrophage inhibition as a contributing factor in the potency of systemic dual inhibition of PTPN1 and PTPN2 against cancer.
    Keywords:  LysM‐Cre; PTPN1; PTPN2; macrophages; proinflammation; protein tyrosine phosphatases
    DOI:  https://doi.org/10.1096/fj.202402405R
  5. Int J Mol Sci. 2025 Apr 11. pii: 3621. [Epub ahead of print]26(8):
      Matrix metalloproteinases (MMPs) are key enzymes involved in extracellular matrix (ECM) remodeling, regulating a wide range of cellular and immune processes in both homeostatic and pathological conditions. Host-microbiota interactions play a critical role in maintaining ECM balance; however, during dysbiosis, this regulation is disrupted, leading to compromised barrier integrity, pathogen translocation into circulation, and the development of systemic diseases and cancer. This review highlights the bidirectional relationship between MMP expression/activity and microbiota dysbiosis, emphasizing tissue-specific alterations in MMP activity that contribute to disease progression. In addition, it integrates interdisciplinary evidence to illustrate the MMP-dependent mechanisms underlying various pathologies associated with oral and gut microbiome dysbiosis, including long-range effects through the gut-skin and gut-brain axes. Thus, this review introduces the emerging field of MatrixBiome, which explores the complex interactions between the ECM, microbiota, and host tissues. Finally, it also outlines therapeutic strategies to modulate MMP levels, either indirectly through microbiome-targeted approaches (e.g., prebiotics, probiotics, and postbiotics) or directly using MMP inhibitors, offering promising avenues for future clinical interventions.
    Keywords:  extracellular matrix; matrix metalloproteinases; matrixbiome; microbiome
    DOI:  https://doi.org/10.3390/ijms26083621
  6. Acta Physiol (Oxf). 2025 Jun;241(6): e70051
       AIM: Amino acids, sugars, short-chain fatty acids (SCFA), vitamins, and other small molecules compose the extracellular metabolome on the airway lumen surface, but how the airway epithelium deals with these molecules has not been deeply studied. Due to the broad spectrum of metabolites transported by SLC5A8 and SLC5A12, we aim to determine if they are functionally expressed and participate in the absorption of Na+, short-chain fatty acids, and monocarboxylates in mouse and human airway epithelium.
    METHODS: Tracheas isolated from male or female mice and human bronchial epithelial cells (HBECs) were used for electrophysiological studies in the Ussing chamber and to detect members of the SLC16 family by RT-PCR and bulk RNAseq. Additionally, cell lines expressing the human and murine SLC5A8 transporter were employed for uptake studies using a fluorescent lactate probe.
    RESULTS: We showed for the first time that human and murine airway epithelium express a functional SLC5A8 transporter, facilitating the absorption of glucose metabolites and SCFAs. The Na+-coupled monocarboxylate transport was not additive with ENaC-mediated Na+ absorption in mouse trachea. We observed that valproate acts as an inhibitor of the murine but not of the human SLC5A8 transporter.
    CONCLUSIONS: Our results demonstrate that several metabolites derived from bacterial and cellular metabolism can be transported from the airway lumen into the epithelial cells, participating in a homeostatic relation of the tissue with its environment.
    Keywords:  L‐lactate; SCFA; SLC5A9; SMCT1; airways
    DOI:  https://doi.org/10.1111/apha.70051
  7. Pathogens. 2025 Apr 15. pii: 386. [Epub ahead of print]14(4):
      Staphylococcus aureus is a formidable pathogen notorious for its antibiotic resistance and diverse virulence mechanisms, including toxin production, biofilm formation, and immune evasion. This article explores innovative anti-virulence strategies to disarm S. aureus by targeting critical virulence factors without exerting bactericidal pressure. Key approaches include inhibiting adhesion and biofilm formation, neutralizing toxins, disrupting quorum sensing (e.g., Agr system inhibitors), and blocking iron acquisition pathways. Additionally, interventions targeting two-component regulatory systems are highlighted. While promising, challenges such as strain variability, biofilm resilience, pharmacokinetic limitations, and resistance evolution underscore the need for combination therapies and advanced formulations. Integrating anti-virulence strategies with traditional antibiotics and host-directed therapies offers a sustainable solution to combat multidrug-resistant S. aureus, particularly methicillin-resistant strains (MRSA), and mitigate the global public health crisis.
    Keywords:  QS inhibition; Staphylococcus aureus; adhesion and biofilm inhibition; anti-virulence strategies; toxin neutralization
    DOI:  https://doi.org/10.3390/pathogens14040386
  8. Cell Discov. 2025 May 05. 11(1): 42
      Caspases are critical regulators of cell death, development, innate immunity, host defense, and disease. Upon detection of pathogens, damage-associated molecular patterns, cytokines, or other homeostatic disruptions, innate immune sensors, such as NLRs, activate caspases to initiate distinct regulated cell death pathways, including non-lytic (apoptosis) and innate immune lytic (pyroptosis and PANoptosis) pathways. These cell death pathways are driven by specific caspases and distinguished by their unique molecular mechanisms, supramolecular complexes, and enzymatic properties. Traditionally, caspases are classified as either apoptotic (caspase-2, -3, -6, -7, -8, -9, and -10) or inflammatory (caspase-1, -4, -5, and -11). However, extensive data from the past decades have shown that apoptotic caspases can also drive lytic inflammatory cell death downstream of innate immune sensing and inflammatory responses, such as in the case of caspase-3, -6, -7, and -8. Therefore, more inclusive classification systems based on function, substrate specificity, or the presence of pro-domains have been proposed to better reflect the multifaceted roles of caspases. In this review, we categorize caspases into CARD-, DED-, and short/no pro-domain-containing groups and examine their critical functions in innate immunity and cell death, along with their structural and molecular mechanisms, including active site/exosite properties and substrates. Additionally, we highlight the emerging roles of caspases in cellular homeostasis and therapeutic targeting. Given the clinical relevance of caspases across multiple diseases, improved understanding of these proteins and their structure-function relationships is critical for developing effective treatment strategies.
    DOI:  https://doi.org/10.1038/s41421-025-00791-3
  9. Cell Metab. 2025 May 06. pii: S1550-4131(25)00210-4. [Epub ahead of print]37(5): 1046-1048
      Macrophages are responsible for sensing, phagocytosing, and destroying bacteria, yet the metabolic fate of these internalized microbes remains largely unexplored. A recent study published by Lesbats et al. in Nature1 uncovers how macrophages recycle some of the components from phagolysosomal degradation, using them as intermediates in various anabolic pathways and as fuel for oxidative phosphorylation.
    DOI:  https://doi.org/10.1016/j.cmet.2025.03.018
  10. Front Mol Biosci. 2025 ;12 1564176
      Pulmonary fibrosis (PF) is a progressive and lethal interstitial lung disease characterized by aberrant scar formation and destruction of alveolar architecture. Dysfunctional alveolar epithelial cells (AECs) play a central role in initiating PF, where chronic injury triggers apoptosis and disrupts epithelial homeostasis, leading to epithelial-mesenchymal transition (EMT). This dynamic reprogramming process causes AECs to shed epithelial markers and adopt a mesenchymal phenotype, fueling fibroblast activation and pathological extracellular matrix (ECM) deposition. This review systematically explores the multi-layered mechanisms driving AECs dysfunction and EMT, focusing on core signaling axes such as transforming growth factor-β (TGF-β)/Smad, WNT/β-catenin, NF-κB-BRD4, and nuclear factor erythroid 2-related factor 2 (Nrf2), which regulate EMT and fibroblast-ECM interactions. It also highlights emerging regulators, including metabolic reprogramming, exosomal miRNA trafficking, and immune-epithelial interactions. Furthermore, understanding these mechanisms is essential for developing targeted therapeutic strategies to modulate these pathways and halt or reverse fibrosis progression, offering critical insights into potential clinical treatments for PF.
    Keywords:  alveolar epithelial cell; epithelial-mesenchymal transition; molecular mechanisms; pulmonary fibrosis; signaling pathways
    DOI:  https://doi.org/10.3389/fmolb.2025.1564176
  11. Acc Chem Res. 2025 May 07.
      ConspectusMethodological development in the fields of genetics, chemical biology, and biochemistry over the last several decades has provided researchers with a diverse set of powerful tools to investigate biological processes. Leveraging these innovations in concert, scientists can now characterize biological pathways at a level of complexity ranging from systems biology down to molecular and atomic detail.Throughout this Account, we illustrate how discoveries made using these tools build on each other to develop a comprehensive understanding of biological pathways. Advancements in genetic sequencing facilitates association of genotypes and phenotypes, independent of biochemical mechanism. Through the biochemical reconstitution of the interactions between biological macromolecules─including the small molecules (ligands and metabolites) and proteins─that participate in these biological pathways, scientists can characterize the specific molecular features that link genotype and phenotype. This facilitates identification of targets within these pathways that can be manipulated to achieve a greater understanding of the biological process or to develop interventions to improve human health outcomes.Specifically, we describe how this toolbox was leveraged to discover and characterize the molecular biochemistry underlying control of pathogenicity in the Gram-positive bacterium Staphylococcus aureus. Concurrent with advancements in the investigative tools available to the scientific community, we and others reported on the genetic, molecular, and biochemical/biophysical components of this regulatory system. Virulence control in S. aureus is achieved through a chemical system of bacterial cell-to-cell communication indexed to local population density, referred to as quorum sensing (QS). We and our collaborators identified that this QS system is encoded in the accessory gene regulator (agr) operon and functions via the biosynthesis, secretion, and accumulation of a short peptide signaling molecule─the autoinducing peptide (AIP)─in the local environment correlated with the growth of S. aureus in the same biological niche. Above a threshold concentration, these AIPs bind and activate a cell-surface receptor to stimulate an intracellular response resulting in altered gene expression and bacterial group behaviors. We discovered that chemical modification of these AIPs often generates molecules that exhibit potent inhibition of agr QS, with demonstrated therapeutic potential to treat S. aureus infections. We went on to characterize the biochemical mechanism of signaling molecule biosynthesis and receptor activation in controlled systems through in vitro reconstitution of the constituent enzymes and substrates. Biochemical reconstitution enabled quantitative assessment of biophysical parameters. These efforts culminated in the comprehensive characterization and functional in vitro reconstitution of agr QS in a synthetic system in a minimal model at the interface of genotype, mechanism, and phenotype.
    DOI:  https://doi.org/10.1021/acs.accounts.5c00117
  12. J Biol Chem. 2025 May 05. pii: S0021-9258(25)02052-6. [Epub ahead of print] 110203
      Pathological fibrosis, the excessive deposition of extracellular matrix and tissue stiffening that causes progressive organ dysfunction, underlies diverse chronic diseases. The fibrotic microenvironment is driven by the dynamic microenvironmental interaction between various cell types; macrophages and fibroblasts play central roles in fibrotic disease initiation, maintenance, and progression. Macrophage functional plasticity to microenvironmental stimuli modulates fibroblast functionality by releasing pro-inflammatory cytokines, growth factors, and matrix remodeling enzymes that promote fibroblast proliferation, activation, and differentiation into myofibroblasts. Activated fibroblasts and myofibroblasts serve as the fibrotic effector cells, secreting extracellular matrix components and initiating microenvironmental contracture. Fibroblasts also modulate macrophage function through the release of their own pro-inflammatory cytokines and growth factors, creating bidirectional crosstalk that reinforces the chronic fibrotic cycle. The intricate interplay between macrophages and fibroblasts, including their secretomes and signaling interactions, leads to tissue damage and pathological loss of tissue function. In this review, we examine macrophage-fibroblast reciprocal dynamic interactions in pathological fibrotic conditions. We discuss the specific lineages and functionality of macrophages and fibroblasts implicated in fibrotic progression, with focus on their signal transduction pathways and secretory signalling that enables their pro-fibrotic behaviour. We then finish with a set of recommendations for future experimentation with the goal of developing a set of potential targets for anti-fibrotic therapeutic candidates. Understanding the cellular interactions between macrophages and fibroblasts provides valuable insights into potential therapeutic strategies to mitigate fibrotic disease progression.
    Keywords:  Extracellular Matrix; Fibroblasts; Fibrosis; Inflammation; Macrophages
    DOI:  https://doi.org/10.1016/j.jbc.2025.110203
  13. Front Immunol. 2025 ;16 1547559
       Introduction: The microenvironment of Candida albicans biofilms create a hypoxic microenvironment, which exerts a profound influence on host immune responses during infection. Neutrophils are key defenders against C. albicans; however, the impact of biofilm-induced hypoxia on neutrophil function remains unclear.
    Methods: We co-cultured human neutrophils in vitro with C. albicans biofilms at various stages of maturation, using both wild-type strains and extracellular matrix (ECM)-deficient mutants. Intracellular hypoxia was assessed using a fluorescent oxygen-sensitive probe. Neutrophil effector functions were evaluated by measuring caspase-3/7 activity, stabilization of hypoxia-inducible factor 1-alpha (HIF-1α), and accumulation of the anti-apoptotic Mcl-1 protein. Analyses included also quantification of reactive oxygen species (ROS) production, neutrophil extracellular trap (NET) formation, chemokine secretion (IL-8 and MIP-1β), and neutrophil elastase release. To assess the role of hypoxia signaling in neutrophil responses, cells were treated with the selective HIF-1α inhibitors LW6 and PX478.
    Results: Neutrophils infiltrating C. albicans wild-type biofilms experience progressive hypoxia, which intensifies with biofilm maturation. This hypoxia results from high fungal metabolic activity and extracellular matrix (ECM) production. Within the biofilm microenvironment, neutrophils exhibit increased stabilization of HIF-1α and Mcl-1, elevated secretion of MIP-1β, IL-8, and reduced caspase 3/7 activity, collectively suggesting a biofilm-induced pro-survival phenotype. Simultaneously, mature biofilms markedly suppress NET formation and ROS production while enhancing degranulation. Comparative analyses using mannan-deficient C. albicans mutants highlight the critical role of ECM composition in modulating hypoxia-driven immune responses. Pharmacological inhibition of HIF-1α with LW6 and PX478 partially restores NETosis and ROS production, underscoring the pivotal role of this protein in regulation of neutrophil function.
    Discussion: These findings provide novel insights into the impact of biofilm-induced hypoxia on neutrophil responses, identifying HIF-1α as a key regulator of immune adaptation in fungal biofilms. Targeting hypoxia pathways may offer new therapeutic strategies to modulate neutrophil responses and enhance host defenses against fungal infections.
    Keywords:  Candida albicans; HIF-1α; biofilms; hypoxia; neutrophils
    DOI:  https://doi.org/10.3389/fimmu.2025.1547559
  14. J Vis Exp. 2025 Apr 18.
      Cells of the monocyte-macrophage lineage are multifunctional and found in almost all body tissues. They coordinate innate and adaptive immunity´s initiation and resolution phases, significantly affecting protective immunity and immune-mediated pathological injury. While tissue-resident macrophages are key players in maintaining homeostasis in a steady state, large amounts of monocytes are recruited from the peripheral blood into the tissue following damage or inflammatory insults. Monocyte-derived macrophages (M-DM) can differentiate into many dynamic subtypes, and their phenotypes and functions depend on the local tissue environment. To compare different stimuli or environmental conditions during M-DM differentiation and polarization, we standardized an in-vitro model of human nonpolarized M-DM M0 and some cardinal cytokine-polarized macrophages, IFNγ/LPS-derived M1, IL-4-derived M2a, and IL-10 or dexamethasone-derived M2c, to analyze skewing reprogramming of M-DM by flow cytometry and real-time PCR. We found that CD64, CD206, CD163, CD14, and MERTK can clearly discriminate unpolarized M0 and polarized M1, M2a, and M2c by flow cytometry. Moreover, we defined IRF1 and CXCL10 as specific genes for classical IFNγ/LPS-derived M1-, IRF4-, CCL22-, and TGM2-specific transcripts for IL-4-derived M2a, and the MERTK gene for dexamethasone-derived M2c. To summarize, our standardized M-DM protocol could give the cardinal in-vitro map to analyze the differentiation and polarization of human M-DM under diverse stimuli.
    DOI:  https://doi.org/10.3791/67651
  15. Int J Mol Sci. 2025 Apr 11. pii: 3630. [Epub ahead of print]26(8):
      Increased abundance of Segatella copri (S. copri) within the gut microbiota is associated with systemic inflammatory diseases, including rheumatoid arthritis. Although outer-membrane vesicles (OMVs) of Gram-negative bacteria are important players in microbiota-host communication, the effect of S. copri-derived OMVs on immune cells is unknown. Macrophages engulf and eliminate foreign material and are conditioned by environmental signals to promote either homeostasis or inflammation. Thus, we aimed to explore the impact of S. copri-OMVs on human macrophages in vitro, employing THP-1 and monocyte-derived macrophage models. The uptake of DiO-labeled S. copri-OMVs into macrophages was monitored by confocal microscopy and flow cytometry. Furthermore, the effect of S. copri and S. copri-OMVs on the phenotype and cytokine secretion of naïve (M0), pro-inflammatory (M1), and anti-inflammatory (M2) macrophages was analyzed by flow cytometry and ELISA, respectively. We show that S. copri-OMVs enter human macrophages through macropinocytosis and clathrin-dependent mechanisms. S. copri-OMVs, but not the parental bacterium, induced a dose-dependent increase in the expression of M1-related surface markers in M0 and M2 macrophages and activated the secretion of large amounts of pro-inflammatory cytokines in M1 macrophages. These results highlight an important role of S. copri-OMVs in promoting pro-inflammatory macrophage responses, which might contribute to systemic inflammatory diseases.
    Keywords:  M1/M2 polarization; Segatella copri; endocytosis; macrophages; outer-membrane vesicles
    DOI:  https://doi.org/10.3390/ijms26083630
  16. J Nanobiotechnology. 2025 May 03. 23(1): 328
       BACKGROUND: Non-healing chronic wounds with high susceptibility to infection represent a critical challenge in modern healthcare. While growth factors play a pivotal role in regulating chronic wound repair, their therapeutic efficacy is compromised in infected microenvironments. Current wound dressings inadequately address the dual demands of sustained bioactive molecule delivery and robust antimicrobial activity.
    RESULTS: In this study, we developed a sodium alginate hydrogel (termed P-SA/Ins), which incorporated polyhexamethylene biguanide (PHMB) grafting and long-acting glargine insulin loading. P-SA/Ins exhibited the favorable physicochemical performance, biocompatibility and antibacterial efficacy against both Gram-negative and Gram-positive pathogens through inhibition of bacterial proliferation and biofilm formation. Glargine insulin was applied to prolonged insulin delivery. P-SA/Ins treatment attenuated S. aureus induced pro-inflammatory cytokine cascades in macrophages. The evaluation in vivo using a rat model with S. aureus infected wound demonstrated that P-SA/Ins significantly enhanced wound healing and optimized skin barrier through antimicrobial-mediated modulation of macrophage polarization and subsequent inflammatory cytokine profiling.
    CONCLUSIONS: Our findings demonstrate that P-SA/Ins promotes wound healing and restores epidermal barrier integrity, indicating its potential as a therapeutic dressing for chronic wound healing, particularly in cases with infection risk.
    Keywords:  Infected wound healing; Inflammation regulation; Insulin; PHMB; Skin barrier
    DOI:  https://doi.org/10.1186/s12951-025-03398-8
  17. Int J Mol Sci. 2025 Apr 08. pii: 3469. [Epub ahead of print]26(8):
      Metabolic diseases, including cardiovascular diseases, type 2 diabetes mellitus (T2DM), osteoporosis, and non-alcoholic fatty liver disease (NAFLD), constitute a major global health burden associated with chronic morbidity and mortality. Lactate, once considered as a metabolic byproduct, has emerged as a key regulator of cellular reprogramming through lactylation, a novel post-translational modification (PTM) that dynamically couples metabolic flux to chromatin remodeling. Lactylation exerts dual regulatory roles as a signaling molecule via GPR81/GPR4-mediated pathways and as a substrate for the covalent modification of histones and metabolic enzymes. Pathologically, chronic hyperlactatemia suppresses mitochondrial biogenesis, driving metabolic cardiomyopathy through the epigenetic silencing of oxidative metabolism genes. Conversely, exercise-induced lactate surges transiently enhance insulin sensitivity via AMPK/PGC-1α/GLUT4 signaling, resolve inflammation through GPR81-mediated M2 macrophage polarization, and restore mitochondrial function via lactylation-dependent pathways. This review delineates lactylation as a spatiotemporal rheostat: chronic dysregulation perpetuates metabolic disorders, whereas acute exercise-mediated lactylation remodels transcriptional networks to restore metabolic homeostasis. Future research should integrate multiomics to clarify lactylation's spatiotemporal dynamics, tissue-specific thresholds, metabolism-immunity interactions, and metabolic-epigenetic crosstalk for the precision management of metabolic diseases.
    Keywords:  epigenetic regulation; exercise therapy; insulin resistance; lactate; lactylation; metabolic reprogramming
    DOI:  https://doi.org/10.3390/ijms26083469
  18. Immunology. 2025 May 04.
      Alveolar macrophages (AMs) are the most numerous immune cells of the lung and are the resident, sentinel lung immunocytes that summon trafficking immune cells to the compartment. Immune profiling of AMs from COVID-19 patients implicates AMs in the immune circuits that drive pulmonary inflammation in severe COVID-19 infection. However, little is known about human AM responses to SARS-CoV-2 proteins, such as the spike protein and envelope protein. We aimed to understand if human AMs recognize SARS-CoV-2 proteins and how they respond. We found that human AMs do not sense SARS-CoV-2 spike protein but do sense envelope protein via the pattern recognition receptors TLR2 and TLR4, secreting IL-1β, IFNγ, IL-12p70, IL-6, and TNFα in response. AMs from donors over the age of 70 years produced significantly more cytokines than those from younger patients following stimulation with SARS-CoV-2 envelope protein. AMs from current smokers had lower cytokine secretion. This is the first report of human AMs producing cytokines in response to SARS-CoV-2 proteins and the first to correlate those responses with clinical risk factors. These results may partly explain why older adults are at such high risk of severe lung inflammation in COVID-19.
    Keywords:  COVID‐19; SARS‐CoV‐2; age; macrophage; risk factors; smoking
    DOI:  https://doi.org/10.1111/imm.13922
  19. J Burn Care Res. 2025 May 04. pii: iraf069. [Epub ahead of print]
      Burn trauma triggers dysregulated systemic inflammation, leading to multi-organ dysfunction. Respiratory failure often follows burn injury, resulting in morbidity and mortality, in part, because of excessive and prolonged release of local and systemic pro-inflammatory mediators. One class of important mediators of inflammation at mucosal surfaces are antimicrobial peptides (AMPs), and their expression is notably altered in inflammation. We sought to determine whether pulmonary AMPs are induced in inflammatory lung after burn. C57BL/6 male mice were given a 12-15% full thickness total body surface area dorsal scald burn or sham injury. Survival rate and pulmonary function of the mice were assessed at 24 hours. Histopathological examination and quantification of pro-inflammatory mediators, IL-6 and CXCL1, in the lungs at 24 hours after burn were performed. mRNA expression of a subset of prominent lung AMPs in whole lung, alveolar macrophages, and primary lung epithelial cells were measured. Our data showed decreased survival and impaired respiratory function after burn injury. Moreover, hematoxylin and eosin-stained lung sections of burned mice showed pulmonary edema and congestion, and pulmonary IL-6 and CXCL1 were elevated. AMP analysis revealed that burn triggered a dramatic rise in lung Camp and S100a8 above that of sham mice. To our surprise, lung epithelial cells, and not alveolar macrophages, were the cellular source of burn-induced Camp and S100a8 in this murine model of burn injury. Taken together, these data reveal for the first time that lung inflammation post-burn involves a rise in AMPs, Camp and S100a8, from lung epithelial cells.
    Keywords:  S100a8; antimicrobial peptide; burn; cathelicidin-related antimicrobial peptide; lung
    DOI:  https://doi.org/10.1093/jbcr/iraf069
  20. Regen Ther. 2025 Jun;29 474-483
      Concentrated growth factor (CGF) is widely applied in clinical practice, but whether it has bone promoting effects and its mechanism of action are still the focus of discussion. In this study, in vitro experiments demonstrate that CGF can promote the expression of Arg-1 in BMDM cells, facilitating their polarization towards the M2 macrophages and encouraging the secretion of IL-10 and VEGF-A. CGF modulates M1 macrophages by reducing the expression of iNOS, while enhancing Arg-1 expression, thereby converting them to M2 macrophages. This is accompanied by a decrease in the secretion of TNF- α and IL-1β, and an increase in the secretion of IL-10 and VEGF-A. Mechanistically, CGF promotes the phosphorylation of STAT3, which in turn induces M2 macrophage polarization, suggesting that the function of CGF-mediated macrophages may be associated with the STAT3 signaling pathway. Moreover, CGF-mediated macrophages were found to enhance osteoblast activity, increasing the expression of ALP, RUNX2, and BMP-2, and improving cell migration capabilities. In vivo experiments showed that CGF could early recruit M2 macrophages to the bone defect site, promoting the expression of bone formation-related proteins such as ALP and BMP-2, and accelerating bone tissue regeneration. In summary, our study demonstrates that CGF can induce bone repair and regeneration by promoting immune modulation and macrophage polarization.
    Keywords:  Bone regeneration; CGF; JAK/STAT; Macrophages
    DOI:  https://doi.org/10.1016/j.reth.2025.04.013
  21. Nat Microbiol. 2025 May 06.
      The gut microbiota may protect against obesity and chronic metabolic conditions by regulating the immune response to dietary triggers. Yet the specific bacteria that control the overactivation of the immune system in obesity and their mode of action remain largely unknown. Here we surveyed 7,569 human metagenomes and observed an association between the gut symbiont Phascolarctobacterium faecium and non-obese adults regardless of nationality, sex or age. In a mouse model of diet-induced obesity, we confirmed the specificity of P. faecium DSM 32890 anti-obesogenic properties compared with other species of the same genus. P. faecium reversed the inflammatory phenotype associated with obesity. Specifically, P. faecium promoted polarization of alternatively activated macrophages (M2), which reversed the obesity-induced increase in gut-resident type 1 innate lymphoid cells. This resulted in mitigation of glucose intolerance, adiposity and body weight gain irrespective of treatment with live or pasteurized bacteria. The metabolic benefits were independent of the adaptive immune system, but they were abolished by an inhibitor of M2 polarization in mice. P. faecium directly promoted M2-macrophage polarization through TLR2 signalling and these effects seemed to be independent of gut microbiota changes. Overall, we identify a previously undescribed gut commensal bacterium that could help mitigate obesity and metabolic comorbidities by retuning the innate immune response to hypercaloric diets.
    DOI:  https://doi.org/10.1038/s41564-025-01989-7