bims-bac4me 2025-04-06 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–04–06
37 papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

Pathogen-derived peptidoglycan skeleton enhances innate immune defense against Staphylococcus aureus via mTOR-HIF-1α-HK2-mediated trained immunity.
Pathogen adaptation to lung metabolites.
Crosstalk between metabolism and epigenetics during macrophage polarization.
M28 family peptidase derived from Peribacillus frigoritolerans initiates trained immunity to prevent MRSA via the complosome-phosphatidylcholine axis.
Setdb2 Regulates Inflammatory Trigger-Induced Trained Immunity of Macrophages Through Two Different Epigenetic Mechanisms.
Microecology in vitro model replicates the human skin microbiome interactions.
Eosinophil innate immune memory after bacterial skin infection promotes allergic lung inflammation.
Alveolar macrophages: guardians of the alveolar lipid galaxy.
Conversation between skin microbiota and the host: from early life to adulthood.
Gang of 3: How the Krebs cycle-linked metabolites itaconate, succinate, and fumarate regulate macrophages and inflammation.
An effective response to respiratory inhibition by a Pseudomonas aeruginosa excreted quinoline promotes Staphylococcus aureus fitness and survival in co-culture.
Identification of the Staphylococcus aureus endothelial cell surface interactome by proximity labeling.
Peroxisomes mediate tissue repair.
Inflammasomes primarily restrict cytosolic Salmonella replication within human macrophages.
Modulation of Host Immunity by Microbiome-Derived Indole-3-Propionic Acid and Other Bacterial Metabolites.
They are what they eat.
Analysis of genetic requirements and nutrient availability for Staphylococcus aureus growth in cystic fibrosis sputum.
Airway epithelial cells as drivers of severe asthma pathogenesis.
Targeting PDK1: A novel approach to combat hypoxia-induced epithelial-mesenchymal transition in chronic rhinosinusitis with nasal polyps.
TAK1 Governs Monocyte-Derived Macrophage Development in Acute Sterile Peritonitis.
BCG-trained macrophages couple LDLR upregulation to type I IFN responses and antiviral immunity.
PLC and PAD2 Regulate Extracellular Calcium-Triggered Release of Macrophage Extracellular DNA Traps.
A tale of two caspases.
The role of metabolite sensors in metabolism-immune interaction: New targets for immune modulation.
Salmonella typhi serine threonine kinase T4519 induces lysosomal membrane permeabilization by manipulating toll-like receptor 2-Cystatin B-Cathepsin B-NF-κB-reactive oxygen species pathway and promotes survival within human macrophages.
Streptococcus anginosus Activates the NLRP3 Inflammasome to Promote Inflammatory Responses from Macrophages.
Life-long microbiome rejuvenation improves intestinal barrier function and inflammaging in mice.
Healthy and premature aging of monocytes and macrophages.
Metabolic Reprogramming in Stromal and Immune Cells in Rheumatoid Arthritis and Osteoarthritis: Therapeutic Possibilities.
Synergistic induction of PGE2 by oral pathogens and TNF promotes gingival fibroblast-driven stromal-immune cross-talk in periodontitis.
Edaravone alleviates Pseudomonas aeruginosa associated-acute lung injury by inhibiting inflammation and promoting anti-microbial peptide production.
Resident tissue macrophages maintain intraocular pressure by regulating extracellular matrix homeostasis.
FTO Aggravates the Infiltration of Inflammatory Cells and Pulmonary Fibrosis in Silicosis Though Inducing the Imbalance of Macrophages Polarization.
Gut flora-derived succinate exacerbates Allergic Airway Inflammation by promoting protein succinylation.
Association of mucosal neutrophil inflammation and cytokine responses with natural and experimental pneumococcal carriage in a randomised vaccine trial using experimental human pneumococcal carriage.
Pyroptosis of pulmonary fibroblasts and macrophages through NLRC4 inflammasome leads to acute respiratory failure.
Birth and household exposures are associated with changes to skin bacterial communities during infancy.

Microbiol Res. 2025 Mar 29. pii: S0944-5013(25)00116-8. [Epub ahead of print]296 128160

Pathogen-derived peptidoglycan skeleton enhances innate immune defense against Staphylococcus aureus via mTOR-HIF-1α-HK2-mediated trained immunity.

Zheng Jia, Lingdi Niu, Junjie Guo, Jiaqing Wang, Hai Li, Runhang Liu, Ning Liu, Shuhe Zhang, Fang Wang, Junwei Ge.

  Regulation of the innate immune response may be an effective strategy to enhance Staphylococcus aureus vaccines. Based on our previous findings that the Listeria peptidoglycan skeleton (pBLP) enhances the immune response through an unknown mechanism, we hypothesized that pBLP provides protection by modulating the innate immune response via trained immunity. In vitro, pBLP increased phagocytosis and inflammatory cytokine levels and elevated the anti-inflammatory cytokine TGF-β following secondary stimulation. In an in vivo model, our findings indicate that pBLP, when administered with a vaccine, protects mice from methicillin-resistant S. aureus challenge and also provides protection against S. aureus CMCC26003 in the absence of antigens. Using an ex vivo model, we demonstrated that pBLP increases markers of trained immunity in peritoneal macrophages. Transcriptome analysis of differentially expressed genes and inhibitor experiments revealed that the trained immunity process induced by pBLP depends on mTOR-HIF-1α and hexokinase 2. This study is the first to demonstrate that pBLP can induce trained immunity. Furthermore, we show that the peptidoglycan skeleton induces a distinct trained immunity phenotype compared to β-glucan, enhancing vaccine protection. Our study provides valuable insights for the design of novel vaccines that integrate both specific and innate immune responses.

Keywords:  Innate immunity; Metabolic reprogramming; Methicillin-resistance; Peptidoglycan skeleton; Staphylococcus aureus; Trained immunity

DOI:  https://doi.org/10.1016/j.micres.2025.128160
Curr Opin Microbiol. 2025 Apr 02. pii: S1369-5274(25)00030-X. [Epub ahead of print]85 102608

Pathogen adaptation to lung metabolites.

Gaurav Kumar Lohia, Sebastián A Riquelme.

Opportunistic pathogens like Pseudomonas aeruginosa and Staphylococcus aureus rapidly adapt to the dynamic metabolic landscape of the respiratory mucosa during infection. Host phagocytes recognize these pathogens and trigger metabolic reprogramming, releasing immunometabolites such as succinate and itaconate. P. aeruginosa preferentially consumes succinate as a carbon source to enhance planktonic growth. In response to itaconate-induced membrane stress, it forms protective biofilms, allowing bacterial survival despite host defenses. Additionally, host ketone bodies support microbial communities that are less immunostimulatory and better tolerated by the lung. Similarly, S. aureus responds to itaconate by forming biofilms, aiding colonization in glucose-limited airways. In this milieu, S. aureus consumes proline, linking its survival with the metabolic activity of proline-producing fibroblasts. Here, we will review the competence of both P. aeruginosa and S. aureus to hijack host metabolic pathways, underscoring pathogen metabolic plasticity as an essential strategy to thrive in the human lung.

DOI: https://doi.org/10.1016/j.mib.2025.102608
Epigenetics Chromatin. 2025 Mar 29. 18(1): 16

Crosstalk between metabolism and epigenetics during macrophage polarization.

Kangling Zhang, Chinnaswamy Jagannath.

  Macrophage polarization is a dynamic process driven by a complex interplay of cytokine signaling, metabolism, and epigenetic modifications mediated by pathogens. Upon encountering specific environmental cues, monocytes differentiate into macrophages, adopting either a pro-inflammatory (M1) or anti-inflammatory (M2) phenotype, depending on the cytokines present. M1 macrophages are induced by interferon-gamma (IFN-γ) and are characterized by their reliance on glycolysis and their role in host defense. In contrast, M2 macrophages, stimulated by interleukin-4 (IL-4) and interleukin-13 (IL-13), favor oxidative phosphorylation and participate in tissue repair and anti-inflammatory responses. Metabolism is tightly linked to epigenetic regulation, because key metabolic intermediates such as acetyl-coenzyme A (CoA), α-ketoglutarate (α-KG), S-adenosylmethionine (SAM), and nicotinamide adenine dinucleotide (NAD+) serve as cofactors for chromatin-modifying enzymes, which in turn, directly influences histone acetylation, methylation, RNA/DNA methylation, and protein arginine methylation. These epigenetic modifications control gene expression by regulating chromatin accessibility, thereby modulating macrophage function and polarization. Histone acetylation generally promotes a more open chromatin structure conducive to gene activation, while histone methylation can either activate or repress gene expression depending on the specific residue and its methylation state. Crosstalk between histone modifications, such as acetylation and methylation, further fine-tunes macrophage phenotypes by regulating transcriptional networks in response to metabolic cues. While arginine methylation primarily functions in epigenetics by regulating gene expression through protein modifications, the degradation of methylated proteins releases arginine derivatives like asymmetric dimethylarginine (ADMA), which contribute directly to arginine metabolism-a key factor in macrophage polarization. This review explores the intricate relationships between metabolism and epigenetic regulation during macrophage polarization. A better understanding of this crosstalk will likely generate novel therapeutic insights for manipulating macrophage phenotypes during infections like tuberculosis and inflammatory diseases such as diabetes.

Keywords:  Acetylation; Epigenetics; Glucose metabolism; Histones; IFN-γ; IL-13; IL-4; IL10; M1; M2; Macrophage polarization; Macrophages; Metabolism; Methylation; Sirtuins

DOI:  https://doi.org/10.1186/s13072-025-00575-9
Gut Microbes. 2025 Dec;17(1): 2484386

M28 family peptidase derived from Peribacillus frigoritolerans initiates trained immunity to prevent MRSA via the complosome-phosphatidylcholine axis.

Cheng-Kai Zhou, Zhen-Zhen Liu, Zi-Ran Peng, Xue-Yue Luo, Xiao-Mei Zhang, Jian-Gang Zhang, Liang Zhang, Wei Chen, Yong-Jun Yang.

  Methicillin-resistant Staphylococcus aureus (MRSA) represents a major global health threat due to its resistance to conventional antibiotics. The commensal microbiota maintains a symbiotic relationship with the host, playing essential roles in metabolism, energy regulation, immune modulation, and pathogen control. Mammals harbor a wide range of commensal bacteria capable of producing unique metabolites with potential therapeutic properties. This study demonstrated that M28 family peptidase (M28), derived from commensal bacteria Peribacillus frigoritolerans (P. f), provided protective effects against MRSA-induced pneumonia. M28 enhanced the phagocytosis and bactericidal activity of macrophages by inducing trained immunity. RNA sequencing and metabolomic analyses identified the CFB-C3a-C3aR-HIF-1α axis-mediated phosphatidylcholine accumulation as the key mechanism for M28-induced trained immunity. Phosphatidylcholine, like M28, also induced trained immunity. To enhance M28-mediated therapeutic potential, it was encapsulated in liposomes (M28-LNPs), which exhibited superior immune-stimulating properties compared to M28 alone. In vivo experiments revealed that M28-LNPs significantly reduced bacterial loads and lung damage following MRSA infection, which also provided enhanced protection against Klebsiella pneumoniae and Candida albicans. We first confirmed a link between complement activation and trained immunity, offering valuable insights into the treatment and prevention of complement-related autoimmune diseases.

Keywords:  M28 family peptidase; MRSA; Peribacillus frigoritolerans; complosome; phosphatidylcholine; trained immunity

DOI:  https://doi.org/10.1080/19490976.2025.2484386
bioRxiv. 2025 Mar 19. pii: 2025.03.18.644013. [Epub ahead of print]

Setdb2 Regulates Inflammatory Trigger-Induced Trained Immunity of Macrophages Through Two Different Epigenetic Mechanisms.

Anant Jaiswal, Laszlo Halasz, David L Williams, Timothy Osborne.

"Trained immunity" of innate immune cells occurs through a sequential two-step process where an initial pathogenic or sterile inflammatory trigger is followed by an amplified response to a later un-related secondary pathogen challenge. The memory effect is mediated at least in part through epigenetic modifications of the chromatin landscape. Here, we investigated the role of the epigenetic modifier Setdb2 in microbial (β-glucan) or sterile trigger (Western-diet-WD/oxidized-LDL-oxLDL)-induced trained immunity of macrophages. Using genetic mouse models and genomic analysis, we uncovered a critical role of Setdb2 in regulating proinflammatory and metabolic pathway reprogramming. We further show that Setdb2 regulates trained immunity through two different complementary mechanisms: one where it positively regulates glycolytic and inflammatory pathway genes via enhancer-promoter looping, and is independent of its enzymatic activity; while the second mechanism is associated with both increased promoter associated H3K9 methylation and repression of interferon response pathway genes. Interestingly, while both mechanisms occur in response to pathogenic training, only the chromatin-looping mechanism operates in response to the sterile inflammatory stimulus. These results reveal a previously unknown bifurcation in the downstream pathways that distinguishes between pathogenic and sterile inflammatory signaling responses associated with the innate immune memory response and may provide potential therapeutic opportunities to target cytokine vs. interferon pathways to limit complications of chronic inflammation.

DOI: https://doi.org/10.1101/2025.03.18.644013
Nat Commun. 2025 Mar 31. 16(1): 3085

Microecology in vitro model replicates the human skin microbiome interactions.

Pan Wang, Huijuan Li, Xingjiang Zhang, Xiaoxun Wang, Wenwen Sun, Xiaoya Zhang, Baiyi Chi, Yuyo Go, Xi Hui Felicia Chan, Jianxin Wu, Qing Huang.

Skin microecology involves a dynamic equilibrium among the host, microbiome, and internal/external environments. This equilibrium, shaped by multifactorial interactions, reflects individual specificity and diversity. Creating a replicable in vitro skin microecological model is highly challenging. Here, we introduce a mimicked stratum corneum microecology model (SCmic). It uses light cured crosslinked hydrogels as a scaffold and moisture source, and nonviable epidermal cells as the main nutrient. This setup establishes a suitable, stable, and reproducible microecology for microbiome colonization. Notably, it replicates the normal/oily skin microbiota with no significant differences from the original native microbiota at the genus level. Simultaneously, we have developed a standardized human skin microbiota model (Hcm), featuring seven dominant strains that form a representative microbial community. The models provide highly convenient approaches for exploring the intricate mutual interactions among skin microecology, influence of microbiota on skin health, and metabolism of chemical substances by microbiota.

DOI: https://doi.org/10.1038/s41467-025-58377-2
Sci Immunol. 2025 Apr 04. 10(106): eadp6231

Eosinophil innate immune memory after bacterial skin infection promotes allergic lung inflammation.

Mariem Radhouani, Asma Farhat, Anna Hakobyan, Sophie Zahalka, Lisabeth Pimenov, Alina Fokina, Anastasiya Hladik, Karin Lakovits, Jessica Brösamlen, Vojtech Dvorak, Natalia Nunes, Andreas Zech, Marco Idzko, Thomas Krausgruber, Jörg Köhl, Ozge Uluckan, Jiri Kovarik, Kai Hoehlig, Axel Vater, Margret Eckhard, Andy Sombke, Nikolaus Fortelny, Jörg Menche, Sylvia Knapp, Philipp Starkl.

Microbial exposure at barrier interfaces drives development and balance of the immune system, but the consequences of local infections for systemic immunity and secondary inflammation are unclear. Here, we show that skin exposure to the bacterium Staphylococcus aureus persistently shapes the immune system of mice with specific impact on progenitor and mature bone marrow neutrophil and eosinophil populations. The infection-imposed changes in eosinophils were long-lasting and associated with functional as well as imprinted epigenetic and metabolic changes. Bacterial exposure enhanced cutaneous allergic sensitization and resulted in exacerbated allergen-induced lung inflammation. Functional bone marrow eosinophil reprogramming and pulmonary allergen responses were driven by the alarmin interleukin-33 and the complement cleavage fragment C5a. Our study highlights the systemic impact of skin inflammation and reveals mechanisms of eosinophil innate immune memory and organ cross-talk that modulate systemic responses to allergens.

DOI: https://doi.org/10.1126/sciimmunol.adp6231
Curr Opin Lipidol. 2025 Apr 03.

Alveolar macrophages: guardians of the alveolar lipid galaxy.

Isaiah Little, Stephanie Bersie, Elizabeth F Redente, Alexandra L McCubbrey, Elizabeth J Tarling.

   PURPOSE OF REVIEW: As the primary guardians at the air-surface interface, the functional profile of alveolar macrophages (AM) is wide-ranging from establishment of the alveolar niche, homeostatic maintenance of surfactant levels, to pathogen clearance and resolution and repair processes. Alveolar lipid homeostasis is disturbed in chronic lung diseases and contributes to disease pathogenesis through extracellular localization in the alveolar lumen or intracellular accumulation in AM. This review aims to provide a focused overview of the state of knowledge of AM, their ontogeny and development during health and disease, and how dysregulated AM lipids play a key role in disease processes, from initiation to resolution.
RECENT FINDINGS: While lipid-laden macrophages are observed across a broad spectrum of lung diseases, their occurrence has largely been considered consequential. Recent advances in lipidomic profiling of single cell types has revealed that disturbances to lipid homeostasis occur early in disease in tissue-resident cells. Comparisons between inflammatory and fibrotic injury models reveal specific alveolar macrophage subsets with different lipid utilization that contribute to the disease process.
SUMMARY: Understanding the intricate web of AM population seeding and development and how this niche is perturbed by lipid disturbances may help provide leverage for new interventions.

Keywords:  alveolar macrophage; cholesterol; lipid; lung disease

DOI:  https://doi.org/10.1097/MOL.0000000000000987
Exp Mol Med. 2025 Apr 01.

Conversation between skin microbiota and the host: from early life to adulthood.

Jimin Cha, Tae-Gyun Kim, Ji-Hwan Ryu.

Host life is inextricably linked to commensal microbiota, which play a crucial role in maintaining homeostasis and immune activation. A diverse array of commensal microbiota on the skin interacts with the host, influencing the skin physiology in various ways. Early-life exposure to commensal microbiota has long-lasting effects, and disruption of the epidermal barrier or transient exposure to these microorganisms can lead to skin dysbiosis and inflammation. Several commensal skin microbiota have the potential to function as either commensals or pathogens, both influencing and being influenced by the pathogenesis of skin inflammatory diseases. Here we explore the impact of various commensal skin microbiota on the host and elucidate the interactions between skin microbiota and host systems. A deeper understanding of these interactions may open new avenues for developing effective strategies to address skin diseases.

DOI: https://doi.org/10.1038/s12276-025-01427-y
Cell Metab. 2025 Mar 24. pii: S1550-4131(25)00107-X. [Epub ahead of print]

Gang of 3: How the Krebs cycle-linked metabolites itaconate, succinate, and fumarate regulate macrophages and inflammation.

Eva M Pålsson-McDermott, Luke A J O'Neill.

  The reprogramming of metabolic pathways and processes in immune cells has emerged as an important aspect of the immune response. Metabolic intermediates accumulate as a result of metabolic adaptations and mediate functions outside of metabolism in the regulation of immunity and inflammation. In macrophages, there has been a major focus on 3 metabolites linked to the Krebs cycle, itaconate, succinate, and fumarate, which have been shown to regulate multiple processes. Here, we discuss recent progress on these 3 metabolites with regard to their effect on macrophages in host defense and inflammatory diseases. We also consider the therapeutic opportunities presented from the mimicry of these metabolites or by targeting the enzymes that make or metabolize them in order to leverage the body's own anti-inflammatory response.

Keywords:  ETC; Krebs cycle; immunometabolism; immunometabolites; inflammation; therapeutic targets

DOI:  https://doi.org/10.1016/j.cmet.2025.03.004
bioRxiv. 2025 Mar 12. pii: 2025.03.12.642861. [Epub ahead of print]

An effective response to respiratory inhibition by a Pseudomonas aeruginosa excreted quinoline promotes Staphylococcus aureus fitness and survival in co-culture.

Franklin Roman-Rodriguez, Jisun Kim, Dane Parker, Jeffrey M Boyd.

Pseudomonas aeruginosa and Staphylococcus aureus are primary bacterial pathogens isolated from the airways of cystic fibrosis patients. P. aeruginosa produces secondary metabolites that negatively impact the fitness of S. aureus, allowing P. aeruginosa to become the most prominent bacterium when the species are co-cultured. Some of these metabolites inhibit S. aureus respiration. SrrAB is a staphylococcal two-component regulatory system (TCRS) that responds to alterations in respiratory status and helps S. aureus transition between fermentative and respiratory metabolisms. We used P. aeruginosa mutant strains and chemical genetics to demonstrate that P. aeruginosa secondary metabolites, HQNO in particular, inhibit S. aureus respiration, resulting in modified SrrAB stimulation. Metabolomic analyses found that the ratio of NAD + to NADH increased upon prolonged culture with HQNO. Consistent with this, the activity of the Rex transcriptional regulator, which senses and responds to alterations in the NAD + / NADH ratio, had altered activity upon HQNO treatment. The presence of SrrAB increased fitness when cultured with HQNO and increased survival when challenged with P. aeruginosa. S. aureus strains with a decreased ability to maintain redox homeostasis via fermentation had decreased fitness when challenged with HQNO and decreased survival when challenged with P. aeruginosa . These findings led to a model wherein P. aeruginosa secreted HQNO inhibits S. aureus respiration, stimulating SrrAB, which promotes fitness and survival by increasing carbon flux through fermentative pathways to maintain redox homeostasis.
Importance: Cystic fibrosis (CF) is a hereditary respiratory disease that predisposes patients to bacterial infections, primarily caused by Staphylococcus aureus and Pseudomonas aeruginosa . P. aeruginosa excreted secondary metabolites decrease S. aureus fitness during co-infection, ultimately eliminating it. The genetic mechanisms that S. aureus uses to detect and respond to these metabolites are unknown. The S. aureus SrrAB two-component regulatory system senses flux through respiratory pathways and increases transcription of genes utilized for adaption to low-respiration environments. This study demonstrates that SrrAB responds to the P. aeruginosa -produced respiratory toxin HQNO and responds by increasing fermentation increasing competition. This study describes interactions between these two bacterial pathogens, which could be exploited to decrease pathogen burden in individuals living with cystic fibrosis.

DOI: https://doi.org/10.1101/2025.03.12.642861
mBio. 2025 Mar 31. e0365424

Identification of the Staphylococcus aureus endothelial cell surface interactome by proximity labeling.

Marcel Rühling, Fabio Schmelz, Alicia Kempf, Kerstin Paprotka, Martin J Fraunholz.

  Virulence strategies of pathogens depend on interaction with host cells. The binding and activation of receptors located on the plasma membrane are crucial for the attachment to or pathogen internalization by host cells. Identifying host cell receptors is often difficult, and hence, the identity of many proteins that play important roles during host-pathogen interaction remains elusive. We developed a novel proximity labeling approach by decorating the opportunistic pathogen Staphylococcus aureus with ascorbate peroxidase 2. Upon addition of hydrogen peroxide, the peroxidase initiates proximity biotinylation of S. aureus host interaction partners, thereby enabling the identification of these proteins. Here, we demonstrate an endothelial cell surface interactome of 305 proteins, including novel S. aureus co-receptors such as neuronal adhesion molecule, protein tyrosine kinase PTK7, melanotransferrin, protein-tyrosine kinase MET, and CD109. Filtering the interactome for validated surface proteins resulted in a list of 89 protein candidates, 53% of which were described to interact with S. aureus or other pathogens.
IMPORTANCE: Staphylococcus aureus is an opportunistic pathogen that enters host cells such as epithelial or endothelial cells. Intracellular pathogens have been observed in vivo and are thought to serve immune evasion, avoidance of antibiotic treatment, and chronicity of infection. Thus, it is important to understand the mechanisms by which the bacteria are internalized by host cells; however, screening for pathogen-host receptors is difficult. Here, we developed a novel proximity labeling approach, which enabled the identification of several previously unknown host receptors of S. aureus that are engaged during a rapid uptake pathway for the bacteria.

Keywords:  Staphylococcus aureus; host receptor identification; proximity biotinylation

DOI:  https://doi.org/10.1128/mbio.03654-24
Nat Immunol. 2025 Apr;26(4): 528

Peroxisomes mediate tissue repair.

Stephanie Houston.

DOI: https://doi.org/10.1038/s41590-025-02130-w
Elife. 2025 Mar 27. pii: RP90107. [Epub ahead of print]12

Inflammasomes primarily restrict cytosolic Salmonella replication within human macrophages.

Marisa S Egan, Emily A O'Rourke, Shrawan Kumar Mageswaran, Biao Zuo, Inna Martynyuk, Tabitha Demissie, Emma N Hunter, Antonia R Bass, Yi-Wei Chang, Igor E Brodsky, Sunny Shin.

  Salmonella enterica serovar Typhimurium is a facultative intracellular pathogen that utilizes its type III secretion systems (T3SSs) to inject virulence factors into host cells and colonize the host. In turn, a subset of cytosolic immune receptors respond to T3SS ligands by forming multimeric signaling complexes called inflammasomes, which activate caspases that induce interleukin-1 (IL-1) family cytokine release and an inflammatory form of cell death called pyroptosis. Human macrophages mount a multifaceted inflammasome response to Salmonella infection that ultimately restricts intracellular bacterial replication. However, how inflammasomes restrict Salmonella replication remains unknown. We find that caspase-1 is essential for mediating inflammasome responses to Salmonella and restricting bacterial replication within human macrophages, with caspase-4 contributing as well. We also demonstrate that the downstream pore-forming protein gasdermin D (GSDMD) and Ninjurin-1 (NINJ1), a mediator of terminal cell lysis, play a role in controlling Salmonella replication in human macrophages. Notably, in the absence of inflammasome responses, we observed hyperreplication of Salmonella within the cytosol of infected cells as well as increased bacterial replication within vacuoles, suggesting that inflammasomes control Salmonella replication primarily within the cytosol and also within vacuoles. These findings reveal that inflammatory caspases and pyroptotic factors mediate inflammasome responses that restrict the subcellular localization of intracellular Salmonella replication within human macrophages.

Keywords:  Salmonella enterica serovar Typhimurium; human; human macrophages; immunology; infectious disease; inflammasomes; inflammation; microbiology; salmonella enterica serovar typhimurium

DOI:  https://doi.org/10.7554/eLife.90107
Eur J Immunol. 2025 Apr;55(4): e202451594

Modulation of Host Immunity by Microbiome-Derived Indole-3-Propionic Acid and Other Bacterial Metabolites.

Burkhard Schütz, Felix F Krause, R Verena Taudte, Mario M Zaiss, Maik Luu, Alexander Visekruna.

  In recent years, we have witnessed a rapidly growing interest in the intricate communications between intestinal microorganisms and the host immune system. Research on the human microbiome is evolving from merely descriptive and correlative studies to a deeper mechanistic understanding of the bidirectional interactions between gut microbiota and the mucosal immune system. Despite numerous challenges, it has become increasingly evident that an imbalance in gut microbiota composition, known as dysbiosis, is associated with the development and progression of various metabolic, immune, cancer, and neurodegenerative disorders. A growing body of evidence highlights the importance of small molecules produced by intestinal commensal bacteria, collectively referred to as gut microbial metabolites. These metabolites serve as crucial diffusible messengers, translating the microbial language to host cells. This review aims to explore the complex and not yet fully understood molecular mechanisms through which microbiota-derived metabolites influence the activity of the immune cells and shape immune reactions in the gut and other organs. Specifically, we will discuss recent research that reveals the close relationship between microbial indole-3-propionic acid (IPA) and mucosal immunity. Furthermore, we will emphasize the beneficial effects of IPA on intestinal inflammation and discuss its potential clinical implications.

Keywords:  Intestinal microbiota; gut microbial metabolites; indole‐3‐propionic acid; mucosal immune system

DOI:  https://doi.org/10.1002/eji.202451594
Sci Immunol. 2025 Apr 04. 10(106): eadx7179

They are what they eat.

Asha Pillai.

The viability of ingested bacterial pathogens can alter the metabolic program and cytokine secretion of macrophages.

DOI: https://doi.org/10.1126/sciimmunol.adx7179
mBio. 2025 Apr 02. e0037425

Analysis of genetic requirements and nutrient availability for Staphylococcus aureus growth in cystic fibrosis sputum.

Lauren M Shull, Daniel J Wolter, Dillon E Kunkle, Katherine A Legg, David P Giedroc, Eric P Skaar, Lucas R Hoffman, Michelle L Reniere.

  Staphylococcus aureus is one of the most common pathogens isolated from the lungs of people with cystic fibrosis (CF), but little is known about its ability to colonize this niche. We performed a transposon-sequencing (Tn-seq) screen to identify genes necessary for S. aureus growth in media prepared from ex vivo CF sputum. We identified 19 genes that were required for growth in all sputum media tested and dozens more that were required for growth in at least one sputum medium. Depleted mutants of interest included insertions in many genes important for surviving metal starvation, as well as the primary regulator of cysteine metabolism, cymR. To investigate the mechanisms by which these genes contribute to S. aureus growth in sputum, we quantified low-molecular-weight thiols, nutrient transition metals, and the host metal-sequestration protein calprotectin in sputum from 11 individuals with CF. In all samples, the abundance of calprotectin exceeded nutrient metal concentration, explaining the S. aureus requirement for metal-starvation genes. Furthermore, all samples contain potentially toxic quantities of cysteine and sufficient glutathione to satisfy the organic sulfur requirements of S. aureus. Deletion of the cysteine importer genes tcyA and tcyP in the ∆cymR background restored growth to wild-type levels in CF sputum, suggesting that the mechanism by which cymR is required for growth in sputum is to prevent uncontrolled import of cysteine or cystine from this environment. Overall, this work demonstrates that calprotectin and cysteine limit S. aureus growth in CF sputum.IMPORTANCEStaphylococcus aureus is a major cause of lung infections in people with cystic fibrosis (CF). This work identifies genes required for S. aureus growth in this niche, which represent potential targets for anti-Staphylococcal treatments. We show that genes involved in surviving metal starvation are required for growth in CF sputum. We also found that the primary regulator of cysteine metabolism, CymR, plays a critical role in preventing cysteine intoxication during growth in CF sputum. To support these models, we analyzed sputum from 11 individuals with CF to determine concentrations of calprotectin, nutrient metals, and low-molecular-weight thiols, which have not previously been quantified together in the same samples.

Keywords:  Staphylococcus aureus; Tn-seq; calprotectin; cysteine; cystic fibrosis; glutathione; metal sequestration; nutritional immunity; sputum

DOI:  https://doi.org/10.1128/mbio.00374-25
Mucosal Immunol. 2025 Mar 26. pii: S1933-0219(25)00029-7. [Epub ahead of print]

Airway epithelial cells as drivers of severe asthma pathogenesis.

Del Dorscheid, Gail M Gauvreau, Steve N Georas, Pieter S Hiemstra, Gilda Varricchi, Bart N Lambrecht, Gianni Marone.

  Our understanding of the airway epithelium's role in driving asthma pathogenesis has evolved over time. From being regarded primarily as a physical barrier that could be damaged via inflammation, the epithelium is now known to actively contribute to asthma development through interactions with the immune system. The airway epithelium contains multiple cell types with specialized functions spanning barrier action, mucociliary clearance, immune cell recruitment, and maintenance of tissue homeostasis. Environmental insults may cause direct or indirect injury to the epithelium leading to impaired barrier function, epithelial remodelling and increased release of inflammatory mediators. In severe asthma, the epithelial barrier repair process is inhibited and the response to insults is exaggerated, driving downstream inflammation. Genetic and epigenetic mechanisms also maintain dysregulation of the epithelial barrier, adding to disease chronicity. Here, we review the role of the airway epithelium in severe asthma and how targeting the epithelium can contribute to asthma treatment.

Keywords:  Airway epithelium; Asthma pathogenesis; Immune system; Severe asthma

DOI:  https://doi.org/10.1016/j.mucimm.2025.03.003
Clin Transl Allergy. 2025 Apr;15(4): e70048

Targeting PDK1: A novel approach to combat hypoxia-induced epithelial-mesenchymal transition in chronic rhinosinusitis with nasal polyps.

Sicen Pan, Mengyan Zhuang, Xiangdong Wang, Qinqin Zhang, Ting He, Ying Li, Jian Jiao, Luo Zhang.

   BACKGROUND: Hypoxia is a prevalent pathological process in chronic rhinosinusitis with nasal polyps (CRSwNP), leading to a cascade of pathological events, including epithelial-mesenchymal transition (EMT). However, the mechanisms underlying hypoxia-induced EMT remain unclear. This study aims to elucidate the mechanisms driving EMT under hypoxic conditions in CRSwNP.
METHODS: Transcriptome and proteome analyses of hypoxia-treated human nasal epithelial cells (HNECs) were performed to identify key molecules and pathways. The expression of hypoxia-inducible factor-1α (HIF-1α), pyruvate dehydrogenase kinase (PDK1), lactate dehydrogenase A (LDHA), and EMT markers was assessed in nasal tissues from CRSwNP patients. In vitro, cultured HNECs were exposed to hypoxia and lactate, or overexpressed PDK1, to evaluate changes in EMT markers.
RESULTS: Hypoxia activated the glycolysis-related pathway in HNECs, with PDK1 and LDHA identified as significantly upregulated glycolysis-related enzymes. The expression of PDK1 and LDHA was closely correlated with HIF-1α and EMT markers in nasal tissues. Hypoxia induced an increase in PDK1 and LDHA expression, lactate production, and EMT occurrence in HNECs. PDK1 overexpression or lactate stimulation also triggered EMT, while PDK1 inhibition attenuated hypoxia-induced EMT in HNECs.
CONCLUSIONS: This study is the first to reveal that hypoxia-induced activation of PDK1 plays a critical role in regulating EMT by promoting lactate production, thereby providing a potential therapeutic target for CRSwNP.

Keywords:  chronic rhinosinusitis with nasal polyps; epithelial‐mesenchymal transition; hypoxia; lactate; pyruvate dehydrogenase kinase 1

DOI:  https://doi.org/10.1002/clt2.70048
Int Immunol. 2025 Mar 29. pii: dxaf019. [Epub ahead of print]

TAK1 Governs Monocyte-Derived Macrophage Development in Acute Sterile Peritonitis.

Katsuki Iwahori, Kengo Maeda, Hideki Sanjo.

  Monocytes recruited to inflamed tissues differentiate into macrophages, contributing to the resolution of inflammation and tissue repair. However, the mechanisms underlying the development, differentiation, and maturation of these monocyte-derived macrophages (MOMs) remain incompletely understood. Here, we demonstrate that TGFβ-activated kinase 1 (TAK1), a key signaling mediator downstream of various receptors including cytokine receptors and Toll-like receptors, is essential for MOM development. In a zymosan-induced model of acute sterile peritonitis, mice with myeloid-specific deletion of TAK1 exhibited a severe impairment in MOM development within the peritoneal cavity, in contrast to control mice. Blocking death receptor signaling with neutralizing antibodies facilitated the recovery of MOM development in these mice, albeit to a limited extent. We identified a transient population of immediate macrophage precursors differentiating from infiltrating monocytes in the peritoneal cavity. Notably, TAK1-deficient macrophage precursors displayed marked susceptibility to cell death, possibly due to a previously unrecognized mechanism distinct from well-characterized cell death pathways. These findings establish TAK1 as a critical regulator of MOM development and uncover a novel survival mechanism in the macrophage precursors during inflammation.

Keywords:  cell death; cell survival; inflammation; moMAP

DOI:  https://doi.org/10.1093/intimm/dxaf019
Cell Rep. 2025 Apr 01. pii: S2211-1247(25)00264-5. [Epub ahead of print]44(4): 115493

BCG-trained macrophages couple LDLR upregulation to type I IFN responses and antiviral immunity.

Yangdian Lai, Xiaoxu Yang, Dong Wei, Xin Wang, Ruiming Sun, Yunfei Li, Ping Ji, Yujie Bao, Tiancheng Chu, Chenxing Zhang, Qiming Liang, Jie Xu, Xinxin Zhang, Yingying Chen, Ying Wang.

  Trained immunity refers to memory-like responses of innate immune cells when they re-encounter pathogenic stimuli. Bacillus Calmette-Guérin (BCG) vaccination implies enhanced antiviral immunity, whereas the underlying mechanisms remain unclear. Herein, we have uncovered elevated expression of low-density lipoprotein receptor (LDLR) on BCG-trained macrophages with robust type I interferon (IFNI) production and antiviral effects both in vivo and in vitro. Consequently, cholesterol is accumulated in BCG-trained macrophages, leading to the augmentation of NFE2L1 expression and the formation of NFE2L1/IRAK1/TRIM25 complex where TRIM25 mediates IRAK1 K63 polyubiquitination to exaggerate IFNI responses in an RIG-I-dependent manner. We have also observed LDLR+ macrophages displaying heightened IFNI responses in BCG-treated human macrophages. To antagonize LDLR degradation by PCSK9 inhibitors increases IFNI responses in the macrophages and accelerated viral clearance. Our study thus couples LDLR upregulation to antiviral activity in BCG-trained macrophages, making commercial PCSK9 inhibitors potential antiviral indications in clinic.

Keywords:  BCG; CP: Immunology; IRAK1; LDLR; NFE2L1; PCSK9 inhibitor; RIG-I; antiviral infection; cholesterol; trained immunity; type I interferon pathway

DOI:  https://doi.org/10.1016/j.celrep.2025.115493
Eur J Immunol. 2025 Apr;55(4): e202350942

PLC and PAD2 Regulate Extracellular Calcium-Triggered Release of Macrophage Extracellular DNA Traps.

Neha Mishra, Magdalena Mohs, Nico Wittmann, Stefan Gross, Paul R Thompson, Lukas Bossaller.

  Macrophages can respond to infection or cellular stress by forming inflammasomes or by releasing extracellular traps (ETs) of DNA through METosis. While ETs have been extensively studied in neutrophils, there are fewer studies on METosis. We show that extracellular calcium and LPS enable human monocyte-derived macrophages (hMDM) to release extracellular DNA decorated with myeloperoxidase (MPO) and citrullinated histone, alongside ASC aggregation and IL-1ß maturation, indicating NLRP3 inflammasome activation. Compared with m-CSF differentiated macrophages only gm-CSF differentiated macrophages expressed macrophage elastase (MMP12) and METs released by the latter had significantly more bactericidal activity toward E. coli. Mechanistically, phospholipase C and peptidyl arginine deiminase-2 inhibition attenuate MET release. Interestingly, NLRP3 inflammasome blockade by MCC950 had a significant effect on MET release. Finally, MET release was completely blocked by plasma membrane stabilization by punicalagin. Altogether, we demonstrate that extracellular calcium-activated hMDM extrude DNA, containing citrullinated histones, MPO, MMP12, and ASC specks and released METs kill bacteria independent of hMDM phagocytotic activity. We believe that calcium-activated hMDM adds a physiologically relevant condition to calcium ionophore induced cell death that may be important in autoimmunity.

Keywords:  cell death; citrullination; extracellular calcium; inflammasomes; macrophage extracellular DNA traps

DOI:  https://doi.org/10.1002/eji.202350942
Elife. 2025 Mar 31. pii: e106581. [Epub ahead of print]14

A tale of two caspases.

Denise M Monack.

  Macrophages control intracellular pathogens like Salmonella by using two caspase enzymes at different times during infection.

Keywords:  Salmonella enterica serovar Typhimurium; human; human macrophages; immunology; inflammasomes; inflammation

DOI:  https://doi.org/10.7554/eLife.106581
Clin Transl Med. 2025 Apr;15(4): e70294

The role of metabolite sensors in metabolism-immune interaction: New targets for immune modulation.

Qiqing Yang, Ce Guo, Long Zhang.

  Recent advancements in immunometabolism have highlighted the critical role of metabolite sensors in regulating immune responses. Metabolites such as lactate, succinate, itaconate, and β-hydroxybutyrate influence immune cell function by interacting with specific sensors. These metabolites act as signaling molecules, linking cellular metabolic changes to immune responses. Lactate, a metabolite commonly produced under hypoxic conditions, has emerged as a major regulator of innate immunity. Key enzymes, including AARS1 and AARS2, function as intracellular lactate sensors, catalyzing lactylation on proteins like cGAS, which plays a central role in DNA sensing and immune activation. The lactylation of cGAS inhibits its activity, modulating immune responses by balancing inflammation and immune tolerance. Metabolite sensors, like MCT1, also contribute to immune modulation, particularly in cancer and chronic inflammatory diseases. Therapeutically, targeting these sensors offers potential for restoring immune function, especially in cancer immunotherapy. However, challenges in specificity, off-target effects, and long-term safety require further investigation. This article explores the emerging role of metabolite sensors in immune regulation, with a focus on lactate sensors, and outlines potential therapeutic strategies to enhance immune responses in metabolic diseases.

Keywords:  immune modulation; inhibitor research and development; lactylation; metabolite sensors

DOI:  https://doi.org/10.1002/ctm2.70294
PLoS Pathog. 2025 Apr 01. 21(4): e1013041

Salmonella typhi serine threonine kinase T4519 induces lysosomal membrane permeabilization by manipulating toll-like receptor 2-Cystatin B-Cathepsin B-NF-κB-reactive oxygen species pathway and promotes survival within human macrophages.

Swarnali Chakraborty, Debayan Ganguli, Theeya Nagaraja, Animesh Gope, Sudip Dey, Ananda Pal, Rahul Shubhra Mandal, Sudipta Sekhar Das, Santasabuj Das.

Intracellular pathogens of Salmonella spp. survive and replicate within the phagosomes, called Salmonella-containing vacuoles (SCVs) inside macrophage by manipulating phagosomal maturation and phagolysosome formation. While controversies exist about the phagosomal traffic of Salmonella Typhimurium, little studies were carried out with the intracellular survival mechanisms of Salmonella Typhi (S. Typhi). We had previously reported that a eukaryote-like serine/threonine kinase of S. Typhi (T4519) contributes to survival within macrophages and activates host pro-inflammatory signaling pathways regulated by NF-κB. However, neither the mechanisms underlying NF-κB activation nor how it contributes to intracellular survival of S. Typhi were studied. Here we show, by using antibody-mediated blocking and gene knockdown studies that T4519 activates Toll-like receptor 2 (TLR2) signals in the human monocyte-derived macrophages. We computationally predicted the NH2-terminal glycine rich repeat domain of T4519 as the TLR2-binding moiety and confirmed the interaction by co-immunoprecipitation experiment. TLR2-T4519 interaction transcriptionally repressed cystatin B, a cathepsin B inhibitor, leading to the activation of cytosolic cathepsin B, leaked from the lysosomes of the infected cells. Through a series of RT-qPCR, western blotting, gene knockdown, flow cytometry and confocal microscopy studies, we have shown that active cytosolic cathepsin B cleaves IKB-α, resulting in nuclear translocation of NF-κB and transactivation of its target genes, including reactive oxygen species (ROS), which in turn induces lysosomal membrane permeabilization (LMP). TLR2-dependent targeting of the cystatin B-cathepsin B-NF-κB-ROS pathways by T4519, leading to LMP promotes phagosomal survival of S. Typhi. This study describes a unique mechanism of the exploitation of host NF-κB signaling pathways by bacterial pathogens to promote its own persistence within macrophage cells.

DOI: https://doi.org/10.1371/journal.ppat.1013041
bioRxiv. 2025 Mar 14. pii: 2025.03.12.642696. [Epub ahead of print]

Streptococcus anginosus Activates the NLRP3 Inflammasome to Promote Inflammatory Responses from Macrophages.

Anika M Arias, Dakota M Reinartz, Chloe Sairs, Sangeetha Senthil Kumar, Justin E Wilson.

Chronic inflammation and oral dysbiosis are common features of oral squamous cell carcinoma (OSCC). The commensal streptococci, S. anginosus, is increased in oral diseases including OSCC. Our previous work revealed that S. anginosus promotes inflammatory responses from macrophage cell lines, however the molecular mechanism by which S. anginosus interacts with macrophages to instigate this response remains to be investigated. Here, we expand on our previous findings by investigating the effects of S. anginosus infection of primary bone marrow derived macrophages (BMMs) and during in vivo infection. We found S. anginosus activated primary BMMs, which presented an enlarged cellular area, increased NF-κB activation and downstream inflammatory cytokines TNF⍰, IL-6 and IL-1β at 24 hours post infection. S. anginosus viability was dispensable for NF-κB activation, but essential for the induction of downstream inflammatory proteins and cytokines. S. anginosus persisted intracellularly within BMMs and induced the expression of inflammasome sensors AIM2, NLRC4 and NLRP3. Further, BMMs lacking the inflammasome adapter protein ASC ( Asc -/- ) had significantly diminished IL-1β production compared to wild type BMMs, indicating that S. anginosus activated the inflammasome. S. anginosus primarily triggered the inflammasome through NLRP3 as S. anginosus -infected Nlrp3 -/- BMMs and NLRP3 inhibitor (MCC950)-treated wild type BMMs displayed diminished IL-1β production compared to wild type controls. Lastly, S. anginosus -infected Asc -/- and Nlrp3 -/- mice displayed reduced weight loss compared to C57BL/6 mice. These overall findings indicate that S. anginosus replicates within macrophages and promotes a proinflammatory response in part through activation of the NLRP3 inflammasome. brief summary sentence: S. anginosus replicates intracellularly within macrophages and is sensed by the NLRP3 inflammasome to promote proinflammatory response.

DOI: https://doi.org/10.1101/2025.03.12.642696
Microbiome. 2025 Apr 02. 13(1): 91

Life-long microbiome rejuvenation improves intestinal barrier function and inflammaging in mice.

Felix Sommer, Joana P Bernardes, Lena Best, Nina Sommer, Jacob Hamm, Berith Messner, Víctor A López-Agudelo, Antonella Fazio, Georgios Marinos, A Samer Kadibalban, Go Ito, Maren Falk-Paulsen, Christoph Kaleta, Philip Rosenstiel.

   BACKGROUND: Alterations in the composition and function of the intestinal microbiota have been observed in organismal aging across a broad spectrum of animal phyla. Recent findings, which have been derived mostly in simple animal models, have even established a causal relationship between age-related microbial shifts and lifespan, suggesting microbiota-directed interventions as a potential tool to decelerate aging processes. To test whether a life-long microbiome rejuvenation strategy could delay or even prevent aging in non-ruminant mammals, we performed recurrent fecal microbial transfer (FMT) in mice throughout life. Transfer material was either derived from 8-week-old mice (young microbiome, yMB) or from animals of the same age as the recipients (isochronic microbiome, iMB) as control. Motor coordination and strength were analyzed by rotarod and grip strength tests, intestinal barrier function by serum LAL assay, transcriptional responses by single-cell RNA sequencing, and fecal microbial community properties by 16S rRNA gene profiling and metagenomics.
RESULTS: Colonization with yMB improved coordination and intestinal permeability compared to iMB. yMB encoded fewer pro-inflammatory factors and altered metabolic pathways favoring oxidative phosphorylation. Ecological interactions among bacteria in yMB were more antagonistic than in iMB implying more stable microbiome communities. Single-cell RNA sequencing analysis of intestinal mucosa revealed a salient shift of cellular phenotypes in the yMB group with markedly increased ATP synthesis and mitochondrial pathways as well as a decrease of age-dependent mesenchymal hallmark transcripts in enterocytes and TA cells, but reduced inflammatory signaling in macrophages.
CONCLUSIONS: Taken together, we demonstrate that life-long and repeated transfer of microbiota material from young mice improved age-related processes including coordinative ability (rotarod), intestinal permeability, and both metabolic and inflammatory profiles mainly of macrophages but also of other immune cells. Video Abstract.

Keywords:  Aging; Lifespan extension; Microbiome; Rejuvenation

DOI:  https://doi.org/10.1186/s40168-025-02089-8
Front Immunol. 2025 ;16 1506165

Healthy and premature aging of monocytes and macrophages.

Syamantak Basu, Ying Ulbricht, Manuela Rossol.

  Aging is associated with immunosenescence, a decline in immune functions, but also with inflammaging, a chronic, low-grade inflammation, contributing to immunosenescence. Monocytes and macrophages belong to the innate immune system and aging has a profound impact on these cells, leading to functional changes and most importantly, to the secretion of pro-inflammatory cytokines and thereby contributing to inflammaging. Rheumatoid arthritis (RA) is an autoimmune disease and age is an important risk factor for developing RA. RA is associated with the early development of age-related co-morbidities like cardiovascular manifestations and osteoporosis. The immune system of RA patients shows signs of premature aging like age-inappropriate increased production of myeloid cells, accelerated telomeric erosion, and the uncontrolled production of pro-inflammatory cytokines. In this review we discuss the influence of aging on monocytes and macrophages during healthy aging and premature aging in rheumatoid arthritis.

Keywords:  aging; immunosenescence; inflammaging; macrophages; monocyte metabolism; monocytes; rheumatoid arthritis

DOI:  https://doi.org/10.3389/fimmu.2025.1506165
Eur J Immunol. 2025 Apr;55(4): e202451381

Metabolic Reprogramming in Stromal and Immune Cells in Rheumatoid Arthritis and Osteoarthritis: Therapeutic Possibilities.

Órlaith C Henry, Luke A J O'Neill.

  Metabolic reprogramming of stromal cells, including fibroblast-like synoviocytes (FLS) and chondrocytes, as well as osteoclasts (OCs), are involved in the inflammatory and degenerative processes underlying rheumatoid arthritis (RA) and osteoarthritis (OA). In RA, FLS exhibit mTOR activation, enhanced glycolysis and reduced oxidative phosphorylation, fuelling inflammation, angiogenesis, and cartilage degradation. In OA, chondrocytes undergo metabolic rewiring, characterised by mTOR and NF-κB activation, mitochondrial dysfunction, and increased glycolysis, which promotes matrix metalloproteinase production, extracellular matrix (ECM) degradation, and angiogenesis. Macrophage-derived immunometabolites, including succinate and itaconate further modulate stromal cell function, acting as signalling molecules that modulate inflammatory and catabolic processes. Succinate promotes inflammation whilst itaconate is anti-inflammatory, suppressing inflammatory joint disease in models. Itaconate deficiency also correlates inversely with disease severity in RA in humans. Emerging evidence highlights the potential of targeting metabolic processes as promising therapeutic strategies for connective tissue disorders.

Keywords:  arthritis; inflammation; metabolic reprogramming; metabolism; rheumatology

DOI:  https://doi.org/10.1002/eji.202451381
mBio. 2025 Apr 03. e0004625

Synergistic induction of PGE2 by oral pathogens and TNF promotes gingival fibroblast-driven stromal-immune cross-talk in periodontitis.

Elwira Nieboga, Aureliusz Schuster, Dominika M Drapala, Mariia Melnykova, Aleksander Gut, Weronika Lipska, Mateusz Kwitniewski, Marcin Migaczewski, Marta Czesnikiewicz-Guzik, Tomasz Kaczmarzyk, Jan Potempa, Aleksander M Grabiec.

  The interaction between pathogenic microorganisms and stromal cells, in particular fibroblasts, significantly contributes to the pathogenesis of many bacterially driven diseases. In periodontitis, oral pathogens penetrate the epithelial barrier and aggravate ongoing gingival inflammation by promoting the production of inflammatory mediators, such as prostaglandin E2 (PGE2). This study aimed to investigate the functional consequences of the interplay between oral pathogens and a pro-inflammatory environment in the activation of the PGE2 pathway in primary human gingival fibroblasts (GFs). GF infection with Fusobacterium nucleatum, Porphyromonas gingivalis, or Filifactor alocis in the presence of tumor necrosis factor (TNF) led to synergistic induction of cyclooxygenase-2 (COX-2), a key enzyme in the PGE2 synthesis pathway, as well as secretion of PGE2. A similar synergy in COX-2 upregulation was observed upon GF infection with oral pathogens in the presence of IL-1α, IL-1β, and interferon-α (IFN-α). This effect required toll-like receptor-2 (TLR2) and the p38 MAP kinase activation and was specific for fibroblasts as infection of macrophages or keratinocytes with oral pathogens in the proinflammatory environment did not cause synergistic COX-2 induction. Finally, we demonstrated that conditioned media from GFs infected with F. nucleatum under inflammatory conditions amplified the expression of the neutrophil chemokine IL8 in macrophages and confirmed that this effect was mediated by synergistic induction of PGE2 in GFs. Collectively, we identify a new mechanism of stromal-immune cross-talk that is driven by synergistic PGE2 induction by oral pathogens and inflammatory cytokines in GFs and may contribute to excessive macrophage activation and neutrophil infiltration in periodontitis.IMPORTANCEPeriodontitis is a highly prevalent, dysbiosis-driven chronic inflammatory disease that not only leads to tooth loss but also is associated with severe systemic diseases. In this work, we describe a novel mechanism responsible for excessive production of PGE2, which is a potent inflammatory mediator that significantly contributes to the pathogenesis of periodontitis. We found that infection of GFs with many species of oral pathogens in the presence of inflammatory cytokines produced by the host leads to synergistic induction of COX-2 expression and PGE2 production. We found that this fibroblast-specific amplification of the COX-2-PGE2 axis by oral pathogens and cytokines is driven by the p38 MAP kinase and promotes enhanced expression of a key neutrophil chemokine by macrophages. These studies have thus enabled the identification of a new mechanism of host-pathogen interactions in periodontitis, improving our understanding of the roles of GFs and their cross-talk with immune cells in disease pathogenesis.

Keywords:  Porphyromonas gingivalis; host-pathogen interactions; inflammation; periodontitis; prostaglandin

DOI:  https://doi.org/10.1128/mbio.00046-25
Int Immunopharmacol. 2025 Mar 29. pii: S1567-5769(25)00501-6. [Epub ahead of print]154 114511

Edaravone alleviates Pseudomonas aeruginosa associated-acute lung injury by inhibiting inflammation and promoting anti-microbial peptide production.

Juan Song, Lin Tong, Jian Xu, Yufan Li, Yingying Zeng, Cuicui Chen, Jian Wang, Yuanlin Song.

  Acute respiratory distress syndrome (ARDS) is the most common respiratory emergency and one of the most severe clinical syndromes. Bacterial and viral infections are the frequent etiological factors. Pseudomonas aeruginosa (PA) is the most significant gram-negative pathogen associated with pneumonia and ARDS in critically ill patients with respiratory diseases. However, multi-drug resistance and biofilm formation pose significant challenges to the clinical treatment of PA-associated pulmonary infections. In this study, we focused on edaravone (EDA), a brain-protective agent and free-radical scavenger commonly used in neurology, and examined its role in PA-ALI. We found EDA significantly mitigated pulmonary pathological damage, inflammatory responses and Reactive Oxygen Species (ROS) generation induced by PA in vivo. The in-vitro assays revealed EDA inhibited the transcription and secretion of pro-inflammatory factors induced by PA in RAW264.7 cells by targeting the TLR4/MyD88/NF-κB signaling pathways. Additionally, EDA reduced the production of intracellular ROS and cell death. EDA treatment enhanced the transcription of antimicrobial peptides, including defensin beta 1 (Defb1), defensin beta 2 (Defb2), CC motif chemokine ligand 20 (Ccl20), secretory leukocyte peptidase inhibitor (Slpi), and lactotransferrin (Ltf), with a significant upregulation of Defb1 expression. We also explored the role of EDA in lung endogenous stem cells using Sftpc-DreER; Scgb1a1-CreER; R26-TLR mice. Our findings indicated that EDA promoted the regeneration of club cells in response to PA stimulation by promoting their proliferation. And also, EDA inhibited PA infection induced cell apoptosis in lung tissues. In conclusion, EDA acts as a protective agent in PA-ALI. It not only inhibits inflammatory responses induced by PA but also enhances the expression of antimicrobial peptides and promotes club cell regeneration. Therefore, EDA may serve as an adjunctive treatment for PA-ARDS.

Keywords:  Acute lung injury; Anti-microbial peptides; Edaravone; Inflammation; Pseudomonas aeruginosa

DOI:  https://doi.org/10.1016/j.intimp.2025.114511
Nat Rev Immunol. 2025 Mar 28.

Resident tissue macrophages maintain intraocular pressure by regulating extracellular matrix homeostasis.

Alex Lac, Slava Epelman.

DOI: https://doi.org/10.1038/s41577-025-01163-4
Microbiol Immunol. 2025 Apr 01.

FTO Aggravates the Infiltration of Inflammatory Cells and Pulmonary Fibrosis in Silicosis Though Inducing the Imbalance of Macrophages Polarization.

Jian-Min Fan, Xu Zhang.

  Silicosis is a lung disease that is very harmful. This makes the disease worse. This study looks at how the fat mass and obesity associated (FTO) gene affects macrophage M1/M2 polarisation and pulmonary fibrosis in silicosis. Macrophages were isolated from alveolar lavage fluid in silicosis and bronchiectasis (BE) patients. Gene expression was detected by reverse transcription-PCR (RT-PCR). Pulmonary fibrosis was assessed by CTFLV/TLV% using 3D CT and Masson staining assay. Enzyme-linked immunosorbent assay was applied to assess inflammatory factor level. The macrophage M1/M2 polarization characteristics (iNOS, CD206) was quantified by Immunofluorescence and Flow cytometry assays. Silicosis patients alveolar lavage macrophages polarized towards M1 type, and the expression level of M1 polarization-related chemokines also increased. More importantly, FTO gene downregulation promotes macrophage polarization to M1 type and the secretion of pro-inflammatory factor TNF-α and IL-6. And FTO knockdown can strengthen the glycolysis of macrophages, especially anaerobic glycolysis, thus inducing macrophages M1 polarization. Moreover, downregulation of FTO ameliorates silicosis pulmonary fibrosis. And FTO upregulation is associated with the M2 polarization of macrophage and the deterioration of pulmonary fibrosis in silicosis patients. FTO downregulation facilitates the infiltration of inflammatory cells by promoting M1 polarization of macrophages in silicosis.

Keywords:  FTO; m6A RNA modification; macrophage polarization; pulmonary fibrosis; silicosis

DOI:  https://doi.org/10.1111/1348-0421.13216
Redox Biol. 2025 Mar 28. pii: S2213-2317(25)00136-3. [Epub ahead of print]82 103623

Gut flora-derived succinate exacerbates Allergic Airway Inflammation by promoting protein succinylation.

Chao Wang, Xin Yu, Xiao Yu, Hui Xiao, Yuemeng Song, Xinlei Wang, Haoyu Zheng, Kai Chen, Yiming An, Zhengjie Zhou, Xiaoping Guo, Fang Wang.

  Allergic airway inflammation (AAI) is a prevalent respiratory disorder that affects a vast number of individuals globally. There exists a complex interplay among inflammation, immune responses, and metabolic processes, which is of paramount importance in the pathogenesis of AAI. Metabolic dysregulation and protein translational modification (PTM) are well-recognized hallmarks of diseases, playing pivotal roles in the onset and progression of numerous ailments. However, the role of gut microbiota metabolites in the development of AAI, as well as their influence on PTM modifications within this disease context, have not been thoroughly explored and investigated thus far. In AAI patients, succinate was identified as a key metabolite, positively correlated with certain immune parameters and IgE levels, and having good diagnostic value. In AAI mice, gut bacteria were the main source of high succinate levels. Mendelian randomization showed succinate as a risk factor for asthma. Exogenous succinate worsened AAI in mice, increasing airway resistance and inflammatory factor levels. Protein succinylation in AAI mice lungs differed significantly from normal mice, with up-regulated proteins in metabolic pathways. FMT alleviated AAI symptoms by reducing succinate and protein succinylation levels. In vitro, succinate promoted protein succinylation in BEAS-2B cells, and SOD2 was identified as a key succinylated protein, with the K68 site crucial for its modification and enzyme activity regulation. Gut flora-derived succinate exacerbates AAI in mice by increasing lung protein succinylation, and FMT can reverse this. These findings offer new insights into AAI mechanisms and potential therapeutic targets.

Keywords:  Allergic airway inflammation; Gut flora; Succinate; Succinylation

DOI:  https://doi.org/10.1016/j.redox.2025.103623
Clin Immunol. 2025 Apr 01. pii: S1521-6616(25)00064-6. [Epub ahead of print] 110489

Association of mucosal neutrophil inflammation and cytokine responses with natural and experimental pneumococcal carriage in a randomised vaccine trial using experimental human pneumococcal carriage.

Gift Chiwala, Raphael Kamng'ona, Evaristar Kudowa, Godwin Tembo, Mphatso Mayuni, Lorensio Chimgoneko, Morrison Kamanga, Faith Thole, Tiyamike Nthandira, Bridgette Galafa, Glory Kadzanja, Tarsizio Chikaonda, John Ndaferankhande, Anthony Chirwa, Edna Nsomba, Lumbani Makhaza, Innocent Sulani, Alfred Muyaya, Neema Toto, Marc Y R Henrion, Dingase Dula, Gareth Lipunga, Ben Morton, Peter Banda, Kondwani Jambo, Stephen B Gordon.

   BACKGROUND: Mucosal inflammation is associated with increased nasal pneumococcal colonisation, but the specific mechanisms are not fully understood. We aimed to find innate immune factors associated with pneumococcal carriage using a controlled human infection model.
METHODS: Healthy Malawian adults participating in a randomised trial of pneumococcal conjugate vaccine (PCV13) were inoculated with one of three doses of Streptococcus pneumoniae 6B. We categorised the participants into 4 pneumococcal carriage outcome groups - no carriage; natural carriage only; experimental carriage; and dual carriage. We then measured neutrophil to lymphocyte ratio (NLR) in nasal mucosa and cytokine levels in nasal lining fluid at 7 days before and 2, 7 and 14 days after inoculation.
FINDINGS: We found that 45 % of participants had no carriage, 35 % had natural carriage, 12 % experimental carriage only and 8 % dual carriage. At 2- and 7-days post inoculation, all groups showed an increase in NLR compared to 7 days before inoculation, accompanied by small changes in cytokine levels. An early increase in NLR was associated with protection against experimental carriage while cytokines did not associate with carriage pattern.
CONCLUSION: Nasal inoculation with S. pneumoniae 6B induced mild, mucosal inflammation but established carriage was not pro-inflammatory. This suggests that nasal inoculation as a vaccine strategy could be asymptomatic.

Keywords:  Controlled human infection model (CHIM); Dual carriage; Natural carriage; Neutrophil to lymphocyte ratio; Respiratory mucosa

DOI:  https://doi.org/10.1016/j.clim.2025.110489
Cell Rep. 2025 Mar 29. pii: S2211-1247(25)00250-5. [Epub ahead of print]44(4): 115479

Pyroptosis of pulmonary fibroblasts and macrophages through NLRC4 inflammasome leads to acute respiratory failure.

Yan Zhang, Guoying Zhang, Brittany Dong, Ankit Pandeya, Jian Cui, Samuel Dos Santos Valenca, Ling Yang, Jiaqian Qi, Zhuodong Chai, Congqing Wu, Daniel Kirchhofer, Toshihiko Shiroishi, Fadi Khasawneh, Min Tao, Feng Shao, Christopher M Waters, Yinan Wei, Zhenyu Li.

  The NAIP/NLRC4 inflammasome plays a pivotal role in the defense against bacterial infections, with its in vivo physiological function primarily recognized as driving inflammation in immune cells. Acute lung injury (ALI) is a leading cause of mortality in sepsis. In this study, we identify that the NAIP/NLRC4 inflammasome is highly expressed in both macrophages and pulmonary fibroblasts and that pyroptosis of these cells plays a critical role in lung injury. Mice challenged with gram-negative bacteria or flagellin developed lethal lung injury, characterized by reduced blood oxygen saturation, disrupted lung barrier function, and escalated inflammation. Flagellin-induced lung injury was protected in caspase-1 or GSDMD-deficient mice. These findings enhance our understanding of the NAIP/NLRC4 inflammasome's (patho)physiological function and highlight the significant role of inflammasome activation and pyroptosis in ALI during sepsis.

Keywords:  CP: Immunology; inflammasome; lung injury; pyroptosis; sepsis

DOI:  https://doi.org/10.1016/j.celrep.2025.115479
Evol Med Public Health. 2025 ;13(1): 49-76

Birth and household exposures are associated with changes to skin bacterial communities during infancy.

Melissa B Manus, Maria Luisa Savo Sardaro, Omolola Dada, Maya Davis, Melissa R Romoff, Stephanie G Torello, Esther Ubadigbo, Rebecca C Wu, Maria Gloria Dominguez-Bello, Melissa K Melby, Emily S Miller, Katherine R Amato.

   Background and objectives: Microbial exposures during infancy shape the development of the microbiome, the collection of microbes living in and on the body, which in turn directs immune system training. Newborns acquire a substantial quantity of microbes during birth and throughout infancy via exposure to microbes in the physical and social environment. Alterations to early life microbial environments may give rise to mismatches, where environmental, cultural and behavioral changes that outpace the body's adaptive responses can lead to adverse health outcomes, particularly those related to microbiome development and immune system regulation.
Methods: This study explored the development of the skin microbiome among infants born in Chicago, USA. We collected skin swab microbiome samples from 22 mother-infant dyads during the first 48 h of life and again at 6 weeks postpartum. Mothers provided information about social environments and hygiene behaviors that may impact infants' microbial exposures.
Results: Analysis of amplicon bacterial gene sequencing data revealed correlations between infant skin bacterial abundances shortly after birth and factors such as antibiotic exposure and receiving a bath in the hospital. The composition of the infant microbiome at 6 weeks of age was associated with interactions with caregivers and infant feeding practices. We also found shifts in maternal skin microbiomes that may reflect increased hygiene practices in the hospital.
Conclusions and implications: Our data suggest that factors related to the birth and household environment can impact the development of infant skin microbiomes and point to practices that may produce mismatches for the infant microbiome and immune system.

Keywords:  Skin microbiome; antibiotics; early life envrionments; mismatches

DOI:  https://doi.org/10.1093/emph/eoae023