bims-bac4me 2025-06-01 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–06–01
sixteen papers selected by
Chun-Chi Chang, Lunds universitet

Human beta defensin-2 protects the epithelial barrier during methicillin-resistant Staphylococcus aureus infection in chronic rhinosinusitis with nasal polyps.
Lactate trains immunity.
TLR2 or TLR4 stimulation induces transmembrane (tm)TNF-driven priming in macrophages which results in improved clearance of a subsequent Staphylococcus aureus infection.
Genome-scale meta-analysis of host responses to Staphylococcus aureus identifies pathways for host-directed therapeutic targeting.
NOD2-induced IκBζ mediates a protective host response against epicutaneous Staphylococcus aureus infection.
Lacticaseibacillus rhamnosus GG-Driven Remodeling of Arginine Metabolism Mitigates Gut Barrier Dysfunction.
Nasal Rinsing with Probiotics-Microbiome Evaluation in Patients with Inflammatory Diseases of the Nasal Mucosa.
Trained immunity in diabetes: emerging targets for cardiovascular complications.
Macrophage-Epithelial Interactions Modulate Epithelial Cell Injury During Airway Reopening.
Redox-signaling in innate immune memory: Similar mechanisms in animals/humans and plants.
WNK1 mediates M-CSF-induced macropinocytosis to enforce macrophage lineage fidelity.
β-Glucan modulates trained immunity to inhibit osteoclast differentiation via NOD2/RIPK2 signaling pathway.
Mast cells activated in vitro can modulate macrophage polarization and antibacterial responses.
Role of Staphylococcus aureus Colonization in Burn Patients.
Complement C1q inhibits the immune escape of mycobacterium tuberculosis associated with macrophage inflammation levels and glycolytic activation.
M1 macrophage inhibits ferroptosis in Pseudomonas aeruginosa-induced kidney epithelial cell injury through the iNOS/ NO pathway without thiol.

Front Cell Infect Microbiol. 2025 ;15 1551080

Human beta defensin-2 protects the epithelial barrier during methicillin-resistant Staphylococcus aureus infection in chronic rhinosinusitis with nasal polyps.

Tengfei Tian, Szuyao Hsu, Qin Sun, Yang Shi, Xianyang Hu, Yang Wu, Keqing Zhao, Chunquan Zheng.

   Objective: We investigated the effect of human beta defensin-2 (hBD-2) on nasal epithelial barrier function with methicillin-resistant Staphylococcus aureus (MRSA) infection in chronic rhinosinusitis with nasal polyps (CRSwNP).
Methods: The expression of hBD-2 was measured in nasal polyps (NPs) from CRSwNP. MRSA was treated with different concentrations of hBD-2 to assess the invasive ability. Primary human nasal epithelial cells (HNECs) cultured at the air-liquid interface (ALI) were pre-incubated with or without hBD-2 prior to MRSA infection. The cell viability, the epithelial cell integrity, and the tight junction (TJ) expression were evaluated.
Results: The expression of hBD-2 in the CRSwNP group was higher than that in the control group. In addition, the hBD-2 protein was negatively correlated with the Lund-Mackay CT score and was positively correlated with the neutrophil levels in CRSwNP. The presence of hBD-2 significantly reduced the invasive ability of MRSA in HNECs. MRSA decreased the epithelial cell integrity by diminishing the protein expression of occludin and zonula occludens-1 (ZO-1). Furthermore, hBD-2 prevented the MRSA-induced barrier disruption by increasing the mucosal permeability and the expression of occludin and ZO-1.
Conclusion: The results suggest that hBD-2 may partially attenuate the epithelial barrier disruption induced by MRSA, indicating the protective effect of hBD-2 on S. aureus infection.

Keywords:  chronic rhinosinusitis with nasal polyps; epithelial barrier; human beta defensin-2; methicillin-resistant Staphylococcus aureus; tight junctions

DOI:  https://doi.org/10.3389/fcimb.2025.1551080
Trends Immunol. 2025 May 26. pii: S1471-4906(25)00123-1. [Epub ahead of print]

Lactate trains immunity.

Alba Llibre, Claudio Mauro.

Understanding the mechanisms implicated in the establishment of trained immunity could aid the design of novel therapeutic approaches. By studying Bacille Calmette-Guerin (BCG) vaccination in a human cohort, Ziogas and colleagues demonstrate the role of lactate generation and its use for histone lactylation as a key mechanism for establishing innate immune memory.

DOI: https://doi.org/10.1016/j.it.2025.05.002
J Innate Immun. 2025 May 28. 1-28

TLR2 or TLR4 stimulation induces transmembrane (tm)TNF-driven priming in macrophages which results in improved clearance of a subsequent Staphylococcus aureus infection.

Abby M Luu, Alexis A Hatton, Jasper Gattiker, Kelly M Shepardson, Monica N Hall, Evelyn Benson, Diane Bimczok, Agnieszka Rynda-Apple.

INTRODUCTION: Toll-like receptor (TLR) engagement on macrophages can improve responsiveness to infection. TNF is upregulated following TLR2 or TLR4 stimulation. We sought to determine whether and how the two bioactive forms of TNF, soluble (sTNF) and transmembrane (tmTNF), may be contributing to macrophage priming, which improved responsiveness to subsequent Staphylococcus aureus infection.
METHODS: RNA sequencing and cytokine quantification assays identified differentially upregulated cytokines in response to TLR2 stimulation. Immortalized and primary bone marrow derived macrophages (BMDMs) coupled with receptor blocking and cytokine supplementation were used to investigate whether/how prior TLR-primed macrophages improved S. aureus clearance.
RESULTS: TLR2 or TLR4 stimulated TNF-/- BMDMs failed to efficiently clear a subsequent S. aureus infection compared to TLR stimulated WT BMDMs. Depletion of sTNF from TLR-stimulated WT BMDMs retained their improved S. aureus clearance. Exogenous sTNF supplementation to TNF-/- BMDMs did not rescue improved S. aureus clearance. Cell density assays showed cell-to-cell contact was important for TLR-induced improvement of S. aureus clearance. Conversely, blocking TNFR2 reduced BMDM clearance of S. aureus, despite TLR2 stimulation.
CONCLUSIONS: Our results demonstrated that TNF produced in response to TLR stimulated BMDMs was required for improved clearance of a subsequent S. aureus infection. We found that sTNF did not contribute to this priming, which suggested that tmTNF may be critical for BMDM priming which leads to improved S. aureus clearance.

DOI: https://doi.org/10.1159/000546011
J Infect Dis. 2025 May 31. pii: jiaf290. [Epub ahead of print]

Genome-scale meta-analysis of host responses to Staphylococcus aureus identifies pathways for host-directed therapeutic targeting.

Clark D Russell, Seraphima Goeldner-Thompson, Emilie Smith, Jonathan E Millar, Bo Wang, Nicholas Parkinson, Sara Clohisey Hendry, Maaike Swets, J Ross Fitzgerald, J Kenneth Baillie, David H Dockrell.

   BACKGROUND: Staphylococcus aureus infections are frequently complicated by metastatic foci, recurrence, and death. Antimicrobial resistance and intracellular bacterial persistence limit the effectiveness of conventional antimicrobials. Host-directed therapies could improve outcomes, but the interpretive complexity of pathogen-host interactions impedes identification of critical responses suitable for therapeutic targeting. To address this, we performed a meta-analysis of genome-scale studies aiming to prioritise host responses to S. aureus.
METHODS: Lists of genes associated with host responses to S. aureus were retrieved from systematically identified genome-scale studies, then integrated using the meta-analysis by information content (MAIC) algorithm. This generated a single aggregated gene list, ranked based on the cumulative evidence supporting each gene.
RESULTS: MAIC prioritised 3867 host genes. Myeloid cell immune responses were enriched with specific hubs including TLR2, IL-17, IFNγ, and IL-1β. Non-canonical effector pathways were also enriched: autophagy (specific factors including mTOR and LAMP2), apoptosis (including BAD and BID), ferroptosis and iron metabolism (TFRC ranked 8/3876), and proteasomal antimicrobial responses (including PSME3 and the novel antimicrobial peptide PPP1CB). Prioritised genes were associated with GWAS traits related to platelet count. In a cohort of patients with S. aureus bacteraemia, platelet count was differentially associated with clinical outcomes. Targets with immediate therapeutic relevance included S. aureus/fibrin/platelet microthrombus formation (VWF, GP11b), S. aureus-induced platelet loss (ASGR2), autophagy (mTOR), BID-mediated apoptosis, and intracellular bacterial killing (IFNγ).
CONCLUSIONS: This in silico analysis identifies cytokine hubs associated with the response to S. aureus infection and prioritises additional host responses including apoptosis, autophagy, iron metabolism, and thrombosis as therapeutic targets.

Keywords:   Staphylococcus aureus ; apoptosis; autophagy; ferroptosis; host-directed therapy; innate immunity; iron; phagocyte; platelet; proteasome

DOI:  https://doi.org/10.1093/infdis/jiaf290
J Invest Dermatol. 2025 May 22. pii: S0022-202X(25)00494-4. [Epub ahead of print]

NOD2-induced IκBζ mediates a protective host response against epicutaneous Staphylococcus aureus infection.

Berenice Fischer, Antonia Kolb, Enrico Focaccia, Tanja Kübelbeck, Matthias Klein, Dagmar Löck, Francesca Bork, Franziska Engelmann, Martina Casari, Elisa Mazza, Carsten Deppermann, Alexander N R Weber, Miriam Wittmann, Birgit Schittek, Klaus Schulze-Osthoff, Daniela Kramer.

  IκBζ, an atypical and largely unknown member of the IκB family, is a transcriptional coactivator of selective immune functions. Here, we investigated the role of keratinocyte-derived IκBζ upon infection with a multidrug-resistant S. aureus strain. Infection of keratinocytes rapidly induced IκBζ expression, leading to an elevated expression of antimicrobial peptides, IL-17/IL-36-responsive genes, and proteins involved in skin barrier function. Conversely, loss of IκBζ resulted in increased S. aureus internalization, epidermal tissue damage, and severe skin infections in vivo. This impaired host defense upon IκBζ depletion was characterized by reduced antimicrobial peptide expression, and diminished recruitment of neutrophils and CD4+ T-cells. Importantly, S. aureus-induced IκBζ expression required the internalization of the bacteria and its sensing by the intracellular receptor NOD2, which triggered IκBζ and its target gene expression. Thus, we identified NOD2-IκBζ signaling as a novel pathway acting as a key mediator for a protective host defense against pathogenic S. aureus infections in the skin.

Keywords:  IκBζ; NFKBIZ; NOD2; Staphylococcus aureus; TLR2; keratinocytes

DOI:  https://doi.org/10.1016/j.jid.2025.04.036
Am J Physiol Gastrointest Liver Physiol. 2025 May 26.

Lacticaseibacillus rhamnosus GG-Driven Remodeling of Arginine Metabolism Mitigates Gut Barrier Dysfunction.

Jayson M Antonio, Yue Liu, Panan Suntornsaratoon, Abby Jones, Jayanth Ambat, Ajitha Bala, Joshua Kanattu, Juan Flores, Sheila Bandyopadhyay, Ravij Upadhyay, Jagannatham Naidu Bhupana, Xiaoyang Su, Wei Vivian Li, Nan Gao, Ronaldo P Ferraris.

  Inflammatory bowel diseases (IBD) and gut barrier impairment are associated with changes in dietary tryptophan and arginine metabolism, but mechanisms of barrier perturbation and restoration are unclear. We show here that the widely consumed probiotic Lacticaseibacillus rhamnosus GG (LGG) enhances gut barrier functions in part through stimulating the intestinal arginine metabolic pathway, and this mechanism depends on the sufficiency of dietary tryptophan in the host. Specifically, LGG markedly upregulates argininosuccinate lyase (ASL), the enzyme that breaks down argininosuccinate into arginine. ASL expression is markedly reduced during experimental colitis with an accumulation of serum argininosuccinate. LGG colonization in mice reduces serum argininosuccinate, a metabolite that inversely correlates with tight junction gene expression, impairs barrier function and exacerbates DSS colitis. We show that LGG-derived indoles as well as arginine metabolites enhanced Asl and Nos2 expression, linking microbial metabolism to nitric oxide production and epithelial homeostasis. IBD patients have increased ASS1 and decreased ASL expression, suggesting a metabolic bottleneck driving ASA accumulation. We propose that signaling pathways underlying LGG and tryptophan mediated ASL upregulation can be useful therapeutic targets to normalize arginine metabolism in select IBD patients.

Keywords:  Inflammatory bowel disease; Intestine; Probiotics; Tight Junction; Tryptophan

DOI:  https://doi.org/10.1152/ajpgi.00366.2024
J Clin Med. 2025 May 11. pii: 3341. [Epub ahead of print]14(10):

Nasal Rinsing with Probiotics-Microbiome Evaluation in Patients with Inflammatory Diseases of the Nasal Mucosa.

Eliza Brożek-Mądry, Laura Ziuzia-Januszewska, Oliwier Misztal, Zofia Burska, Ewelina Sosnowska-Turek, Janusz Sierdziński.

  Background/Objectives: The evidence regarding the efficacy of probiotics in chronic rhinosinusitis (CRS) is very limited, prompting the EPOS2020 steering group to advise against their use in CRS treatment. Therefore, further research to evaluate the impact of probiotics on microbial communities is particularly important. This study aimed to assess the influence of probiotic nasal rinses on nasal microbiota profiles in patients with primary CRS, granulomatosis with polyangiitis (GPA), and nasal septal perforation (NSP) using 16S rRNA sequencing. Methods: Thirty-six patients with nasal mucosal diseases, including sixteen with primary CRS, eleven with GPA, and nine with NSP, were randomly assigned to either a study group receiving nasal rinses with probiotics containing Lactobacillus plantarum and Bifidobacterium animalis, or a control group using nasal rinses with saline. Metagenomic analysis targeting the V3-V4 hypervariable region of the 16S rRNA gene was performed to characterize bacterial and archaeal populations. Results: At the genus level, the most abundant co-colonizers included Staphylococcus, Streptococcus, and Haemophilus. After one month of probiotic rinsing, a decrease in abundance of the genera Finegoldia (p = 0.010), Haemophilus (p = 0.020), Streptococcus (p = 0.027), Staphylococcus (p = 0.033), Micrococcus (p = 0.035), Corynebacterium (p = 0.049), Gemella (p = 0.055), Rubrobacter (p = 0.055), and Pseudonocardia (p = 0.058) was observed. Conversely, the abundance of probiotic species Lactobacillus plantarum and Bifidobacterium animalis increased. Moreover, increases in the genera Dolosigranulum and Stenotrophomonas were observed, although they did not reach statistical significance. Conclusions: Probiotic nasal rinses may contribute to restoring microbial homeostasis by reducing genera associated with inflammatory dysbiosis in nasal inflammatory diseases, warranting further research on their clinical benefits.

Keywords:  chronic rhinosinusitis; granulomatosis with polyangiitis; microbiome; microbiota; nasal rinsing; nasal septal perforation; probiotics

DOI:  https://doi.org/10.3390/jcm14103341
Front Endocrinol (Lausanne). 2025 ;16 1533620

Trained immunity in diabetes: emerging targets for cardiovascular complications.

Yanan Bai, Jianglan Wu, Weixiong Jian.

  Diabetes is a metabolic disorder primarily characterized by persistent hyperglycemia. Diabetes-induced inflammation significantly compromises cardiovascular health, greatly increasing the risk of atherosclerosis. The increasing prevalence of harmful lifestyle habits and overconsumption has contributed substantially to the global rise in diabetes-related cardiovascular diseases, creating a significant economic and healthcare burden. Although current therapeutic strategies focus on blood glucose control and metabolic regulation, clinical observations show that diabetic patients still face persistent residual risk of AS even after achieving metabolic stability. Recent studies suggest that this phenomenon is linked to diabetes-induced trained immunity. Diabetes can induce trained immunity in bone marrow progenitor cells and myeloid cells, thus promoting the long-term development of AS. This article first introduces the concept and molecular mechanisms of trained immunity, with particular emphasis on metabolic and epigenetic reprogramming, which plays a crucial role in sustaining chronic inflammation during trained immunity. Next, it summarizes the involvement of trained immunity in diabetes and its contribution to AS, outlining the cell types that can be trained in AS. Finally, it discusses the connection between diabetes-induced trained immunity and AS, as well as the potential of targeting trained immunity as an intervention strategy. Understanding the molecular mechanisms of trained immunity and their impact on disease progression may provide innovative strategies to address the persistent clinical challenges in managing diabetes and its complications.

Keywords:  atherosclerosis; diabetes; epigenetics; inflammation; metabolism; trained immunity

DOI:  https://doi.org/10.3389/fendo.2025.1533620
J Biomech Eng. 2025 May 29. 1-27

Macrophage-Epithelial Interactions Modulate Epithelial Cell Injury During Airway Reopening.

Tricia Oyster, Vasudha C Shukla, Yuji Tomizawa, Joshua Englert, Megan Ballinger, Samir N Ghadiali.

During the acute respiratory distress syndrome (ARDS), bacterial/viral infections, including COVID-19, lead to significant pulmonary edema and severe hypoxia. Although ARDS patients often require mechanical ventilation (MV), the biophysical forces generated during MV are known to exacerbate lung injury resulting in ventilation-induced lung injury (VILI). During VILI, the complex biomechanical forces generated during the reopening of fluid-occluded airway/alveoli (atelectrauma) causes plasma membrane rupture and epithelial cell death. However, it is not known how the interaction of immune cells, including alveolar macrophages, with epithelial cells alters the degree of atelectrauma. We used in-vitro modeling techniques to investigate how co-culture of both monocyte derived macrophages and primary human alveolar macrophages with lung epithelial cells alter the degree of cell injury during airway reopening. Co-culture of epithelial cells with macrophages led to a significant increase in epithelial cell death/plasma membrane rupture during airway reopening and this increased injury was not due to soluble factors secreted by macrophages. Inhibiting macrophage-epithelial gap junction interactions decreased epithelial cell injury during airway reopening. Morphological and cell biomechanical measurements indicate that epithelial cells in co-culture with macrophages have a lower height-to-width aspect ratio, a lower instantaneous elastic modulus, and a lower power-law exponent. Since lower aspect ratios have been associate with reduced atelectrauma, our data indicate that the reduced stiffness (lower elastic modulus) and increased elasticity (lower power-law exponent) is the biomechanical mechanism by which macrophages exacerbate epithelial cell injury during airway reopening.

DOI: https://doi.org/10.1115/1.4068790
Redox Biol. 2025 May 27. pii: S2213-2317(25)00215-0. [Epub ahead of print]84 103702

Redox-signaling in innate immune memory: Similar mechanisms in animals/humans and plants.

Christian Lindermayr, Ali Önder Yildirim.

  Plants and animals/humans have evolved sophisticated innate immune systems to cope with microbial attack. Innate immunity implies the presence of membrane-located and intracellular receptors to recognize compounds released by damage or by invading pathogens. After detection the receptor molecules initiate intracellular defense signaling, resulting in cell death and/or production of defense molecules. Interestingly, the defense response includes also memory mechanisms, which allow the organisms to better cope with future microbial attacks. Redox mechanisms play an important role in defense signaling. In this review article, we compare the innate immune memory of animals/humans and plants and describe how reversible nitric oxide- and reactive oxygen species-dependent protein modifications enable the activation of defense signaling proteins and transcription factors and regulate the activity of chromatin modifying enzymes to establish innate immune memory. We hope to encourage efforts to characterize further molecular redox mechanisms of the innate immune memory, which might enable the development of new immunotherapies.

Keywords:  Chromatin modulation; Innate immunity; Nitric oxide; Reactive oxygen species; Redox-signaling; Trained immunity

DOI:  https://doi.org/10.1016/j.redox.2025.103702
Nat Commun. 2025 May 28. 16(1): 4945

WNK1 mediates M-CSF-induced macropinocytosis to enforce macrophage lineage fidelity.

Alissa J Trzeciak, Zong-Lin Liu, Mohamed Gatie, Adam S Krebs, Waleska Saitz Rojas, Anya J O'Neal, Ann K Baako, Zhaoquan Wang, Justin Nelson, Isabella C Miranda, Jazib Uddin, Allie Lipshutz, Jian Xie, Chou-Long Huang, Pedro H V Saavedra, Anna-Katerina Hadjantonakis, Michael Overholtzer, Michael S Glickman, Arohan R Subramanya, Thomas Vierbuchen, Jon Iker Etchegaray, Christopher D Lucas, Christopher N Parkhurst, Justin S A Perry.

Tissue-resident macrophages (TRM) are critical for mammalian organismal development and homeostasis. Here we report that with-no-lysine 1 (WNK1) controls myeloid progenitor fate, with Csf1riCre-mediated Wnk1 deletion in mice (WNK1-deficient mice) resulting in loss of TRMs and causing perinatal mortality. Mechanistically, absence of WNK1 or inhibition of WNK kinase activity disrupts macrophage colony-stimulating factor (M-CSF)-stimulated macropinocytosis, thereby blocking mouse and human progenitor and monocyte differentiation into macrophages and skewing progenitor differentiation into neutrophils. Treatment with PMA rescues macropinocytosis but not macrophage differentiation of WNK-inhibited progenitors, implicating that M-CSF-stimulated, macropinocytosis-induced activation of WNK1 is required for macrophage differentiation. Finally, M-CSF-stimulated macropinocytosis triggers WNK1 nuclear translocation and concomitant increased protein expression of interferon regulatory factor (IRF)8, whereas inhibition of macropinocytosis or WNK kinase activity suppresses IRF8 expression. Our results thus suggest that WNK1 and downstream IRF8-regulated genes are important for M-CSF/macropinocytosis-mediated regulation of myeloid cell lineage commitment during TRM development and homeostasis.

DOI: https://doi.org/10.1038/s41467-025-59901-0
Int Immunopharmacol. 2025 May 26. pii: S1567-5769(25)00876-8. [Epub ahead of print]159 114886

β-Glucan modulates trained immunity to inhibit osteoclast differentiation via NOD2/RIPK2 signaling pathway.

Yanjie Li, Mingzhu Chen, Zhenjin Yang, Junxiong Li, Liya Ma, Guangyu Bao, Yanxia Chen, Jiangtian Hu.

   OBJECTIVE: This study investigated how β-glucan (BG)-induced trained immunity (TI) regulates osteoclast-driven bone resorption, with emphasis on the pivotal signaling axis governing this anti-resorptive memory.
METHODS: Bone marrow-derived macrophages (BMMs) were primed with BG for 24 h and subsequently challenged with LPS to establish a TI model, validated by cytokine secretion profiling (IL-1β, IL-6, TNF-α). Osteoclastogenesis was induced by M-CSF/RANKL and assessed via TRAP staining, F-actin ring formation, immunofluorescence for CTSK/MMP-9, and bone resorption assays. Histological evaluation (H&E and TRAP staining) and micro-CT analysis were performed to assess alveolar bone remodeling in a murine periodontitis model. Transcriptomic profiling and functional validation using genetic/pharmacological perturbations identified critical signaling pathways.
RESULTS: BG induced robust TI in macrophages under osteoclastogenic stimuli. Trained BMMs maintained long-term suppression of LPS-driven osteoclast reactivation. Systemic BG preconditioning preserved alveolar bone architecture in vivo. Complete abolition of BG's anti-osteoclastic effects by NOD2/RIPK2 blockade validated the mechanism.
CONCLUSION: BG establishes innate immune memory through NOD2/RIPK2 signaling to counter pathological osteoclast activation, positioning TI modulation as a translational strategy against inflammatory bone loss.

Keywords:  Bone marrow-derived macrophages (BMMs); Nucleotide-binding oligomerization domain-containing protein 2 (NOD2); Osteoclastogenesis; Receptor interacting protein kinase 2 (RIPK2); Trained immunity (TI); β-Glucan (BG)

DOI:  https://doi.org/10.1016/j.intimp.2025.114886
J Allergy Clin Immunol. 2025 May 26. pii: S0091-6749(25)00575-5. [Epub ahead of print]

Mast cells activated in vitro can modulate macrophage polarization and antibacterial responses.

Dorothea B Holter, Sophie Zahalka, Jessica Brösamlen, Mariem Radhouani, Martin L Watzenboeck, Tyler J Artner, Asma Farhat, Riem Gawish, Karin Lakovits, Anastasiya Hladik, Federica Quattrone, Wolfgang Weninger, Thomas Krausgruber, Shane J F Cronin, Shweta Tikoo, Rohit Jain, Sylvia Knapp, Nikolaus Fortelny, Philipp Starkl.

   BACKGROUND: Mast cells and macrophages are tissue-resident immune cells frequently found in close proximity in barrier organs. Macrophages show high plasticity and microenvironmental factors, such as cytokines, can influence their phenotype. Mast cells are central in allergic reactions where allergens cause mast cell activation via antigen-specific IgE antibodies and the release of a multitude of inflammatory substances. While macrophages have clearly defined physiologic roles in tissue maintenance and host defense against microbes, biological mast cell functions are less well defined.
OBJECTIVE: In the current study, we aimed to understand the interplay of mast cells and macrophages and how mast cell-released mediators can shape macrophage phenotype and function.
METHODS: Using primary in vitro models of mast cells and macrophages combined with microscopic, functional, metabolic, genetic and epigenetic analyses, we investigate the macrophage polarization effects of mast cell mediators produced upon activation with IgE and antigen. We apply a macrophage engraftment strategy to explore potential in vivo implications of mast cell-mediated priming.
RESULTS: We find that pre-formed and newly-synthesized mediators released by activated mast cells shape a macrophage phenotype different from the classical M1/M2 macrophage paradigm. Exposure to supernatant of activated mast cells induces epigenetic reprogramming of macrophages. This profound priming effect strongly alters macrophage phagocytosis, cytokine production and transcriptomic responses upon secondary exposure to bacteria or their products. Importantly, in vivo transfer of primed macrophages also significantly affects the outcome of sterile inflammation and bacterial peritonitis.
CONCLUSION: Our study highlights the great potential of activated mast cells as directors of macrophage function.

Keywords:  Allergy; IgE; LPS; activation; bacteria; degranulation; epigenetic; infection; macrophage; mast cell; polarization; priming

DOI:  https://doi.org/10.1016/j.jaci.2025.02.040
J Infect. 2025 May 22. pii: S0163-4453(25)00110-0. [Epub ahead of print] 106516

Role of Staphylococcus aureus Colonization in Burn Patients.

Susanne Sütterlin, Marie Lindblad, Eva Tano, Sara Frosth, Filip Farnebo, Torgny Schennings, Jan-Ingmar Flock, Fredrik Huss.

   OBJECTIVS: Staphylococcus aureus is an important pathogen in burn patients and contributes to mortality, however, the role of colonization with S. aureus in the course of the disease is less well described.
METHODS: The study aimed to determine the frequency of S. aureus colonization in 80 patients treated in a national burn centre in Uppsala, Sweden, during the first ten days of hospitalization in relation to length of stay, number of days before antibiotic treatment started and mortality; additionally, epidemiological relationship and phylogeny were analyzed.
RESULTS: A total of 38/80 (47.5%) patients tested positive for S. aureus upon admission, while 47 out of 65 patients who completed the 10-day study period (72%), were colonized with S. aureus. Patients, that were colonized at admission tended to stay longer at the burn centre, particularly when admitted with more severe conditions corresponding to a rBaux score >70 (p=0.05, R2=0.09). Patients carrying isolates of phylogroup 2 received antibiotic treatment approximately one day later than patients with isolates belonging to phylogroup 1 (p<0.05, R2= 0.09).
CONCLUSIONS: The study findings emphasize that screening for S. aureus colonization in burn patients upon admission, particularly in critically injured patients, could prove beneficial in optimizing antibiotic therapy.

Keywords:  Staphylococcus aureus; burn injury; burn intensive care; colonization; whole-genome sequencing

DOI:  https://doi.org/10.1016/j.jinf.2025.106516
Microb Pathog. 2025 May 27. pii: S0882-4010(25)00482-6. [Epub ahead of print]206 107757

Complement C1q inhibits the immune escape of mycobacterium tuberculosis associated with macrophage inflammation levels and glycolytic activation.

Yan Liu, Jie Wang, Yonglan Pu, Shenjie Tang.

   BACKGROUND: The pathogenic mechanism of mycobacterium tuberculosis (Mtb) is complex, and the immune mechanism of the host against Mtb infection and the escape mechanism of Mtb are not fully understood. This study aimed to explore the mechanisms underlying complement C1q and Mtb immune escape.
METHODS: Functional experiments, using RAW264.7 cells as the focus cell line and applying CCK-8, western blotting, qRT-PCR, and flow cytometry, were carried out to uncover the exact role of C1q in macrophages, glycolytic activation, immune escape, and Mtb.
RESULTS: C1q promoted the proliferation of RAW264.7, suppressed cell apoptosis, and regulated the secretion of M1/M2 type molecular markers in RAW264.7 cells. Moreover, C1q induced glycolytic activation in macrophages, and the immune escape of Mtb in the macrophages was accompanied by the activation of glycolysis.
CONCLUSION: Complement C1q inhibited the immune escape of Mtb associated with macrophage inflammation and glycolytic activation.

Keywords:  C1q; Glycolytic activation; Immune escape; Macrophage; Mycobacterium tuberculosis

DOI:  https://doi.org/10.1016/j.micpath.2025.107757
Front Cell Dev Biol. 2025 ;13 1597160

M1 macrophage inhibits ferroptosis in Pseudomonas aeruginosa-induced kidney epithelial cell injury through the iNOS/ NO pathway without thiol.

Peixiang Lu, Xiaojie Bai, Linfa Guo, Kuerban Tuoheti, Shanzhi Zhan, Tongzu Liu.

   Instruction: Pseudomonas aeruginosa (PA) is one of the common pathogens of urinary tract infection. It can lead to urosepsis and renal damage. However, the mechanism by which P. aeruginosa affects epithelial cells is not clear.
Methods: HK2 cells were treated with extracted PA supernatant (PA.sup). Different pathway inhibitors were added, and similar treatments were applied to HK2 cells co-cultured with macrophages. Cell viability, ferroptosis-related markers, and lipid peroxidation levels were measured.
Results: We found that PA induced lipid peroxidation using its specially secreted 15-lipoxygenase (ploxA), thereby triggering ferroptosis in epithelial cells. And PA can also damage the GPx4/GSH defense system of epithelial cells. This effect is not through the proteasome pathway but through activating lysosomal chaperone-mediated autophagy (CMA) to reduce the host's GPx4 expression. Then macrophages inhibited lipid peroxidation and protected cells lacking GPx4/GSH through iNOS/NO•.
Discussion: We demonstrated that NO• produced by macrophages can remotely prevent PA-induced ferroptosis of renal epithelial cells. When iNOS, which is responsible for NO• production, is pharmacologically inhibited, the antiferroptotic effect of NO• is reduced. In conclusion, our study reveals an intercellular mechanism for inhibiting ferroptosis, which may provide a new strategy for the host to combat P. aeruginosa -induced ferroptosis.

Keywords:  Pseudomonas aeruginosa; epithelial cells; ferroptosis; kidney; macrophage

DOI:  https://doi.org/10.3389/fcell.2025.1597160