bims-bac4me 2025-05-18 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–05–18
twenty-one papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

Therapeutic targeting of the host-microbiota-immune axis: implications for precision health.
Improved humanized mouse model of Staphylococcus aureus infection.
Can probiotics replace antibiotics? Not yet, says the evidence.
Targeted p38 mitogen-activated protein kinase inhibition potently augment inflammatory responses of human macrophages toward Staphylococcus aureus.
Probiotic Lactobacillus species modulate immune responses during vaginal epithelial cell colonization.
Mitochondrial metabolism is rapidly re-activated in mature neutrophils to support stimulation-induced response.
Trained immunity-based Adjuvated vaccines (TIbAV) approach: β-glucans as example.
Immunometabolism of Innate Immune Cells in Gastrointestinal Cancer.
Engineered Tissue Models to Decode Host-Microbiota Interactions.
Candida albicans-stimulated hematopoietic stem and progenitor cells generate trained neutrophils with enhanced mitochondrial ROS production that defend against infection.
Lactate facilitates pancreatic repair following acute pancreatitis by promoting reparative macrophage polarization.
Decoding Macrophage Dynamics: A Pathway to Understanding and Treating Inflammatory Skin Diseases.
Investigating endogenous immune-mediated monocyte memory in rheumatoid arthritis.
Inhibition of TRPV1 attenuates innate nasal epithelial responses via NF-κB signaling pathway in allergic rhinitis.
Reprogramming of GM-CSF-dependent alveolar macrophages through GSK3 activity modulation.
Staphylococcus aureus SaeR/S-regulated factors overcome human complement-mediated inhibition of aggregation to evade neutrophil killing.
Hallmarks of Bacterial Vaginosis.
SERPINB10 promotes macrophage M2 polarization and airway inflammation in asthma.
GPR40 activation alleviates pulmonary fibrosis by repressing M2 macrophage polarization through the PKD1/CD36/TGF-β1 pathway.
New insights into gut microbiota-prostate cancer crosstalk.
Occupationally Relevant Zinc- and Copper-Containing Metal Fumes Inhibit Human THP-1 Macrophage TNF and IL-6 Responses to Bacterial Stimuli.

Front Immunol. 2025 ;16 1570233

Therapeutic targeting of the host-microbiota-immune axis: implications for precision health.

Asiya Nazir, Fathima Hasnain Nadeem Hussain, Tuahir Hassan Nadeem Hussain, Rania Al Dweik, Afsheen Raza.

  The human body functions as a complex ecosystem, hosting trillions of microbes that collectively form the microbiome, pivotal in immune system regulation. The host-microbe immunological axis maintains homeostasis and influences key physiological processes, including metabolism, epithelial integrity, and neural function. Recent advancements in microbiome-based therapeutics, including probiotics, prebiotics and fecal microbiota transplantation, offer promising strategies for immune modulation. Microbial therapies leveraging microbial metabolites and engineered bacterial consortia are emerging as novel therapeutic strategies. However, significant challenges remain, including individual microbiome variability, the complexity of host-microbe interactions, and the need for precise mechanistic insights. This review comprehensively examines the host microbiota immunological interactions, elucidating its mechanisms, therapeutic potential, and the future directions of microbiome-based immunomodulation in human health. It will also critically evaluate challenges, limitations, and future directions for microbiome-based precision medicine.

Keywords:  fecal microbiota transplantation; gut microbiota; microbial dysbiosis; microbiota therapeutics; microbiota-immune interactions; precision medicine and microbiome; probiotics

DOI:  https://doi.org/10.3389/fimmu.2025.1570233
Mucosal Immunol. 2025 May 10. pii: S1933-0219(25)00048-0. [Epub ahead of print]

Improved humanized mouse model of Staphylococcus aureus infection.

Hui Wang, Dane Parker.

  Staphylococcus aureus is a significant cause of pulmonary infections, but existing mouse models fail to recapitulate human-specific responses. In this study, we developed a novel mouse model of S. aureus infection using humanized mice implanted with autologous fetal lung tissue. We show that these human lung implants support S. aureus survival and dissemination. Immunological profiling revealed extensive immune cell death after infection and an absence of chemokine induction. Transcriptomic profiling of the human lung implants revealed significant changes in gene expression, including NF-κB and JAK/STAT signaling. We identified upregulation of Cyp24a1, suggesting a role for vitamin D metabolism in host defense, but it had a mild effect on dissemination. Examination of the bacterial response to the host environment, found downregulation of virulence factors and metabolic genes, and upregulation of stress response pathways. The importance of the heat shock response in bacterial survival was shown as hrcA-deficient S. aureus exhibited reduced tissue colonization. These findings underscore the utility of this humanized lung model for studying S. aureus pathogenesis and bacterial adaptation to the human pulmonary environment.

Keywords:  Humanized mice; Lung; Mouse model; Pneumonia; Staphylococcus aureus

DOI:  https://doi.org/10.1016/j.mucimm.2025.05.001
Expert Rev Anti Infect Ther. 2025 May 14. 1-4

Can probiotics replace antibiotics? Not yet, says the evidence.

Jan Łukasik, Hania Szajewska.



Keywords:  Antibiotics; antibiotic resistance; bacterial infections; gut microbiota; microbiome; probiotics

DOI:  https://doi.org/10.1080/14787210.2025.2499485
Mol Immunol. 2025 May 14. pii: S0161-5890(25)00130-0. [Epub ahead of print]183 145-155

Targeted p38 mitogen-activated protein kinase inhibition potently augment inflammatory responses of human macrophages toward Staphylococcus aureus.

Astrid Lund, David Moffat, Stine Dam Jepsen, Claus Desler, Lars Andresen, Søren Bregenholt, Venkat Reddy, Søren Skov.

  Antibiotic-resistant Staphylococcus aureus (S. aureus) is a growing challenge for human health and novel treatment options are needed. Here we examine a novel therapeutic approach against persistent S. aureus infections based on monocyte/macrophage specific inhibition of the p38α mitogen-activated protein kinase activity. Since systemic p38α kinase inhibition cause aberrant toxicity, we used the myeloid specific p38α kinase inhibitor, MPL-5821. P38α kinase inhibition caused a potent increase in the pro-inflammatory profile of human macrophages after exposure to S. aureus, including upregulation of M1-markers and induction of pro-inflammatory cytokines including IFN-γ, TNF-α, IL-1β, IL12p70, IL-6 and IL-8, as well as an increase in phagocytic capacities. These pro-inflammatory signals were only seen after combined S. aureus exposure and p38α inhibition. Macrophages are often regulated by changes in intracellular metabolism. In agreement with this, the combination of S. aureus exposure and p38α inhibition led to specific changes in glycolytic and mitochondrial activity within the responding macrophages. Our study thus unravels a novel and specific activation of macrophages that augment their response toward S. aureus, without causing aberrant inflammation. This constitutes a unique non-antibiotic therapeutic approach that can potentially be used against persistent S. aureus infection.

Keywords:  Immunology; Macrophage metabolism; Macrophage polarization; Staphylococcus aureus; p38 MAPK inhibition

DOI:  https://doi.org/10.1016/j.molimm.2025.05.010
J Infect Dis. 2025 May 15. pii: jiaf221. [Epub ahead of print]

Probiotic Lactobacillus species modulate immune responses during vaginal epithelial cell colonization.

Marisa Valentine, Diletta Rosati, Axel Dietschmann, Tim B Schille, Mihai G Netea, Bernhard Hube, Mark S Gresnigt.

   BACKGROUND: Vulvovaginal candidiasis (VVC), mainly caused by Candida albicans, affects approximately 75% of women at least once during their lifetime. VVC is characterized by fungal colonization, which leads to inappropriate local hyperinflammation and symptoms. Although the trigger of C. albicans pathogenicity is often unknown, antibiotic use and vaginal dysbiosis are associated with increased susceptibility to VVC. A healthy vaginal microbiota is normally dominated by Lactobacillus species, which are believed to keep C. albicans infections at bay. Probiotic lactobacilli are, therefore, explored to treat symptomatic VVC episodes. However, the influence of probiotic lactobacilli on immune responses in the context of VVC remains underexplored.
METHODS: We investigated how probiotic lactobacilli influence vaginal epithelial and downstream inflammatory responses during C. albicans infection, using in vitro vaginal epithelial infection models and stimulating primary human immune cells with supernatants from these vaginal epithelial cells.
RESULTS: Our study shows that although most of the tested probiotic lactobacilli reduced C. albicans-induced vaginal epithelial cell damage, some species, particularly Limosilactobacillus fermentum and Lacticaseibacillus paracasei, elicited proinflammatory responses even in the absence of C. albicans. Probiotic lactobacilli also differentially modulated the C. albicans killing efficiency and production of reactive oxygen species by neutrophils.
CONCLUSIONS: Overall, vaginal epithelial and downstream immune responses during co-cultivation with C. albicans and probiotic lactobacilli were mostly driven by specific bacterial species and their interactions with the vaginal epithelium. Therefore, the induction of "controlled" inflammation by probiotic lactobacilli may be beneficial to improve neutrophil function, however, whether this alleviates immunopathology warrants further investigation.

Keywords:   Candida albicans ; Lactobacillus ; Vulvovaginal candidiasis; immune response; probiotics

DOI:  https://doi.org/10.1093/infdis/jiaf221
Front Immunol. 2025 ;16 1572927

Mitochondrial metabolism is rapidly re-activated in mature neutrophils to support stimulation-induced response.

Jorgo Lika, James A Votava, Rupsa Datta, Carlos A Mellado Fritz, Aleksandr M Kralovec, Frances M Smith, Anna Huttenlocher, Melissa C Skala, Jing Fan.

   Introduction: Neutrophils are highly abundant innate immune cells that are constantly produced from myeloid progenitors in the bone marrow. Differentiated neutrophils can perform an arsenal of effector functions critical for host defense. This study aims to quantitatively understand neutrophil mitochondrial metabolism throughout differentiation and activation, and to elucidate the impact of mitochondrial metabolism on neutrophil functions.
Methods: To study metabolic remodeling throughout neutrophil differentiation, murine ER-Hoxb8 myeloid progenitor-derived neutrophils and human induced pluripotent stem cell-derived neutrophils were assessed as models. To study the metabolic remodeling upon neutrophil activation, differentiated ER-Hoxb8 neutrophils and primary human neutrophils were activated with various stimuli, including ionomycin, monosodium urate crystals, and phorbol 12-myristate 13-acetate. Characterization of cellular metabolism by isotopic tracing, extracellular flux analysis, metabolomics, and fluorescence-lifetime imaging microscopy revealed dynamic changes in mitochondrial metabolism.
Results: As neutrophils mature, mitochondrial metabolism decreases drastically, energy production is offloaded from oxidative phosphorylation, and glucose oxidation through the TCA cycle is substantially reduced. Nonetheless, mature neutrophils retain the capacity for mitochondrial metabolism. Upon stimulation with certain stimuli, TCA cycle is rapidly activated. Mitochondrial pyruvate carrier inhibitors reduce this re-activation of the TCA cycle and inhibit the release of neutrophil extracellular traps. Treatment with these inhibitors also impacts neutrophil redox status, migration, and apoptosis without significantly changing overall bioenergetics.
Conclusions: Together, these results demonstrate that mitochondrial metabolism is dynamically remodeled and plays a significant role in neutrophils. Furthermore, these findings point to the therapeutic potential of mitochondrial pyruvate carrier inhibitors in a range of conditions where dysregulated neutrophil response drives inflammation and contributes to pathology.

Keywords:  TCA cycle; metabolism; mitochondria; neutrophil; neutrophil extracellular traps

DOI:  https://doi.org/10.3389/fimmu.2025.1572927
Vaccine. 2025 May 10. pii: S0264-410X(25)00537-7. [Epub ahead of print]57 127240

Trained immunity-based Adjuvated vaccines (TIbAV) approach: β-glucans as example.

Miriam Angulo, Abel Ramos-Vega, Carlos Angulo.

  The induction of trained immunity (TRIM) has emerged as an approach to fight against diseases. Several β-glucans and vaccines have been identified as trained immunity inductors, allowing heterologous protection for infectious diseases. Curiously, β-glucans from yeast, fungal, and plant species have been evaluated in clinical trials as vaccine adjuvants to combat infectious and non-communicable diseases. However, their adjuvant use for trained immunity-based vaccines (TIbV) remains scarcely studied. In this context, this review brings a scientific panorama of β-glucans and vaccines and offers perspectives on their combination to potentiate trained immunity induction and its benefits. In agreement with TRIM and TIbV concepts, we propose trained immunity-based adjuvanted vaccines (TIbAV) to refer to studies regarding this approach.

Keywords:  Antigen; Carbohydrate; Health; Innate immune memory; Vaccination

DOI:  https://doi.org/10.1016/j.vaccine.2025.127240
Cancers (Basel). 2025 Apr 27. pii: 1467. [Epub ahead of print]17(9):

Immunometabolism of Innate Immune Cells in Gastrointestinal Cancer.

Izabela Siemińska, Marzena Lenart.

  Cancer cells are often described as voracious consumers of nutrients, with glucose frequently cited as a key energy source; however, their metabolic plasticity allows them to adapt and utilize various substrates, including lipids and amino acids, to sustain growth and survival. However, the metabolic demands of immune cells within the tumor microenvironment (TME) are less commonly discussed despite their critical role in shaping the immune response. In this review, we explored the intricate interplay between immunometabolism and innate immunity cells in gastrointestinal cancers. We focused on how metabolic pathways, including glycolysis, fatty acid oxidation, and amino acid metabolism, drive the immunosuppressive functions of myeloid-derived suppressor cells (MDSCs) and tumor-associated neutrophils (TANs), tumor-associated macrophages (TAMs) and innate lymphocyte subsets such as NK cells. These cells contribute to a hostile immune landscape, supporting tumor growth and evasion from immune surveillance in a phenomenon of tumor-derived immunosuppression. Additionally, we investigated the influence of dietary interventions on the metabolic reprogramming of these immune cells, highlighting how nutrition can modulate the TME. Finally, we discussed emerging therapeutic strategies that target metabolic vulnerabilities in MDSCs, TANs, NK cells, and monocytes, offering a novel avenue for enhancing antitumor immunity. By dissecting these mechanisms, we aim to provide insights into how metabolic pathways can be harnessed to improve cancer treatment outcomes. This review underscores the importance of understanding immunometabolism not only as a driver of immune suppression but also as a potential therapeutic target in gastrointestinal cancer.

Keywords:  colorectal cancer; gastrointestinal cancer; immunometabolism; innate immune cells

DOI:  https://doi.org/10.3390/cancers17091467
Adv Sci (Weinh). 2025 May 14. e2417687

Engineered Tissue Models to Decode Host-Microbiota Interactions.

Miryam Adelfio, Grace E Callen, Xuesong He, Bruce J Paster, Hatice Hasturk, Chiara E Ghezzi.

  A mutualistic co-evolution exists between the host and its associated microbiota in the human body. Bacteria establish ecological niches in various tissues of the body, locally influencing their physiology and functions, but also contributing to the well-being of the whole organism through systemic communication with other distant niches (axis). Emerging evidence indicates that when the composition of the microbiota inhabiting the niche changes toward a pathogenic state (dysbiosis) and interactions with the host become unbalanced, diseases may present. In addition, imbalances within a single niche can cause dysbiosis in distant organs. Current research efforts are focused on elucidating the mechanisms leading to dysbiosis, with the goal of restoring tissue homeostasis. In vitro models can provide critical experimental platforms to address this need, by reproducing the niche cyto-architecture and physiology with high fidelity. This review surveys current in in vitro host-microbiota research strategies and provides a roadmap that can guide the field in further developing physiologically relevant in vitro models of ecological niches, thus enabling investigation of the role of the microbiota in human health and diseases. Lastly, given the Food and Drug Administration Modernization Act 2.0, this review highlights emerging in vitro strategies to support the development and validation of new therapies on the market.

Keywords:  dysbiosis; female reproductive tract; host‐microbiome interactions; intestine; oral; skin; tissue models

DOI:  https://doi.org/10.1002/advs.202417687
PLoS Pathog. 2025 May 13. 21(5): e1013170

Candida albicans-stimulated hematopoietic stem and progenitor cells generate trained neutrophils with enhanced mitochondrial ROS production that defend against infection.

María Sobén, Paula Guerrero, Andrea Guiu, Alberto Yáñez, M Luisa Gil.

Central trained immunity, induced via reprogramming of hematopoietic stem and progenitor cells (HSPCs), mediates sustained heightened responsiveness of mature myeloid cells to secondary challenges. We have previously demonstrated that HSPCs use TLR2 and Dectin-1 to sense Candida albicans to induce the production of trained monocytes/macrophages to fight against secondary infection. Neutrophils play an important role in innate immunity and are critical for clearance of C. albicans. In this work, we used an in vitro model of mouse HSPC differentiation to investigate the functional phenotype of neutrophils derived from HSPCs exposed to various PAMPs and C. albicans cells. We found that neutrophils derived from HSPCs stimulated by a TLR2 agonist exhibit reduced inflammatory cytokine production (tolerized neutrophils) whereas neutrophils generated from a Dectin-1 agonist or C. albicans stimulated HSPCs produce higher amounts of cytokines (trained neutrophils). We further demonstrated that a transient exposure of HSPCs to live C. albicans cells is sufficient to induce a trained phenotype of the neutrophils they produce in a Dectin-1- and TLR2-dependent manner. These trained neutrophils exhibited higher phagocytosis and microbicidal capacity than control neutrophils. Additionally, their adoptive transfer was sufficient to reduce fungal burden during invasive candidiasis. Mechanistically, we demonstrated that trained neutrophils use mitochondrial ROS (mtROS) to enhance their ability to kill C. albicans cells, as they produce higher amounts of mtROS and scavenging mtROS with MitoTEMPO attenuated their yeast-killing ability to match that of control neutrophils. Altogether, these data suggest that infection-experienced HSPCs contribute to trained immunity by providing a source of trained neutrophils with enhanced antimicrobial activity which may confer prolonged protection from infection. The tailored manipulation of this mechanism might offer new therapeutic strategies for controlling fungal infections by harnessing neutrophils.

DOI: https://doi.org/10.1371/journal.ppat.1013170
Cell Mol Gastroenterol Hepatol. 2025 May 09. pii: S2352-345X(25)00076-1. [Epub ahead of print] 101535

Lactate facilitates pancreatic repair following acute pancreatitis by promoting reparative macrophage polarization.

Jing Jiang, Ruiyan Wang, Pengli Song, Qi Peng, Xuerui Jin, Bin Li, Jianbo Ni, Jie Shen, Jingpiao Bao, Zengkai Wu, Xiaolu Ge, Xingpeng Wang, Guoyong Hu.

   BACKGROUND & AIMS: During acute pancreatitis (AP), glycolysis is enhanced. The upregulation of glycolysis increases the level of metabolite lactate. Lactate has been shown to facilitate tissue repair across various pathological conditions. However, its role in the recovery following AP remains unclear. This study aims to explore the role of lactate in the regenerative processes following AP and to elucidate its underlying molecular mechanisms.
METHODS: The caerulein-induced recovery AP model was established using wild type and 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (Pfkfb3) heterozygous mice. Pancreatic repair was evaluated histologically, while lactate levels and inflammatory markers were measured serologically. Macrophages were isolated from pancreatic tissue using fluorescence-activated cell sorting for mRNA sequencing to identify phenotypes. In ex vivo, macrophages were indirectly co-cultured with inflammatory acinar, and the effect of lactate on macrophage phenotype were investigated through immunoprecipitation, fluorescence analysis, and western blotting.
RESULTS: We first found that exogenous lactate administration promoted pancreatic repair, while Pfkfb3 deficiency lowered lactate levels and ultimately delayed pancreatic repair. Mechanistically, lactate altered macrophage phenotype during recovery after AP, by reducing the proportion of pro-inflammatory macrophages and increasing the percentage of reparative macrophages. In the indirectly co-cultured macrophage, lactate increased lactylation levels and enhanced repair gene expression. Treatment with AZD3965, a chemical inhibitor of lactate transportation, blocked the effects on lactylation and gene expression. Besides, lactate repressed the JAK2-STAT1 pathway via GPR132 receptor, thereby suppressing the expression of pro-inflammatory genes.
CONCLUSIONS: Lactate facilitates pancreatic repair by promoting reparative macrophage polarization, achieved through promoting lactylation and inhibiting JAK2-STAT1 signaling. This phenotypic shift alleviates inflammation and facilitates tissue recovery, highlighting a potential therapeutic approach for AP.

Keywords:  lactate; lactylation; macrophage; pancreatic repair

DOI:  https://doi.org/10.1016/j.jcmgh.2025.101535
Int J Mol Sci. 2025 May 01. pii: 4287. [Epub ahead of print]26(9):

Decoding Macrophage Dynamics: A Pathway to Understanding and Treating Inflammatory Skin Diseases.

Shengliang Gu, Lei Xu, Bin Huang, Kai Xiong, Xuesong Yang, Jianzhou Ye.

  Psoriasis and atopic dermatitis (AD) are both chronic inflammatory skin diseases. Their pathogenesis remains incompletely understood. The polarization states of macrophages, as a crucial part of the innate immune system, are influenced by various factors such as cytokines, inflammatory mediators, and epigenetics. Research has demonstrated that macrophages play a "double-edged sword" role in the pathological process of inflammatory skin diseases: they both drive inflammation progression and participate in tissue repair. This article summarizes the roles of macrophages in the inflammatory development and tissue homeostasis of psoriasis and atopic dermatitis. It explores the impact of different factors on macrophages and inflammatory skin diseases. In conclusion, understanding the classification and plasticity of macrophages is crucial for a deeper understanding of the pathogenesis of psoriasis and AD and the development of personalized treatments.

Keywords:  atopic dermatitis; epigenetics; inflammatory dermatosis; macrophage polarization; psoriasis

DOI:  https://doi.org/10.3390/ijms26094287
Ann Rheum Dis. 2025 May 10. pii: S0003-4967(25)00883-0. [Epub ahead of print]

Investigating endogenous immune-mediated monocyte memory in rheumatoid arthritis.

Anna M Marzeda, Anja Schwenzer, Bogdan S Didov, Kieran Woolcock, Jean-Baptiste Richard, Libby K Jennings, Amélie M Julé, Nan Yang, Sarah Davidson, Steve Sansom, Adam P Cribbs, Calliope A Dendrou, Wyatt W Yue, Carl S Goodyear, Karim Raza, Kim S Midwood.

OBJECTIVES: Inflammation triggered by endogenous stimuli that signal cellular stress or tissue injury must be tightly controlled to balance robust protection from intrinsic danger while avoiding catastrophic destruction of healthy tissues. Here, we assess the contribution of innate memory to this balance.
METHODS: Memory evoked by the extracellular matrix protein tenascin-C, a damage-associated, toll-like receptor 4 (TLR4) agonist, was compared to that induced by the pathogenic TLR4 agonist lipopolysaccharide (LPS) by transcriptomic and epigenetic profiling of monocytes from healthy individuals or people wirh rheumatoid arthritis (RA), and tissue macrophages from the RA synovium.
RESULTS: Tenascin-C reprograms monocyte response to subsequent threats, inducing concomitantly suppressed and enhanced responses to rechallenge. Comparative analysis of tenascin-C and LPS revealed common and distinct gene expression signatures, effects controlled transcriptionally and associated with stimulus-specific epigenetic mediators. Altered responses following rechallenge after priming with tenascin-C were not limited to subsequent TLR4 activation but were evident in response to various pathogenic and endogenous stimuli detected by different receptors. In healthy monocytes primed with tenascin-C, rechallenge with stimuli found at high levels in the joints of people with RA resulted in trained responses that were not induced by LPS, including genes associated with chronic inflammation, tissue destruction, altered metabolism, and poor treatment response in RA. The expression of a large subset of these genes was elevated in monocytes from people with RA in the absence of any stimulation and in RA synovial macrophage populations associated with disease flare. Moreover, higher levels of permissive complexes within key epigenetic nodes and increased bivalent modification creating poised loci within endogenously trained genes were observed in RA cells.
CONCLUSIONS: These data highlight how innate reprogramming during 'sterile' inflammatory diseases contributes to chronicity, uncovering pathways unique to endogenous immune triggers that could provide disease-specific points of intervention without engendering global immune suppression.

DOI: https://doi.org/10.1016/j.ard.2025.03.016
Int Immunopharmacol. 2025 May 13. pii: S1567-5769(25)00797-0. [Epub ahead of print]158 114807

Inhibition of TRPV1 attenuates innate nasal epithelial responses via NF-κB signaling pathway in allergic rhinitis.

Yanjie Wang, Xueping Qi, Hanxiong Li, Haoxiang Zhang, Xiaojia Zhu, Luyao Wang, Feiyang Li, Hongying Duan, Sirui Fu, Hedi Zhuo, Fengli Cheng, Changqing Zhao.

   OBJECTIVES: Nasal epithelial cells initiate innate responses to allergens by releasing IL-1 family cytokines, such as IL-33, and disrupting the mucosal barrier. TRPV1 has gained increasing recognition for its role in immune modulation in allergic conditions. This study aimed to elucidate the mechanisms by which epithelial cells detect allergens and explore the pivotal role of TRPV1 in regulating innate nasal epithelial responses.
METHODS: To identify TRPV1-related genes and pathways, the GSE167225 dataset was analyzed. To validate TRPV1 expression, clinical data and nasal tissues from 34 patients with AR and 13 controls were collected. To further investigate its mechanisms, OVA-sensitized C57BL/6 mice were exposed to the TRPV1 antagonist SB-705498, and TRPV1 knockout mice were utilized. Primary human nasal epithelial cells were used for in vitro experiments, and various assays, including reverse transcription polymerase chain reaction(RT-PCR), western blotting(WB), and others, were performed to assess gene expression and signaling pathways.
RESULTS: Bioinformatics and clinical analysis revealed elevated TRPV1 expression in patients with AR, positively correlated with nasal itching and sneezing severity(R = 0.6493, P < 0.001; R = 0.4906, P < 0.001). In vivo, SB-705498 and TRPV1 ablation significantly alleviated allergy symptoms, reduced allergen-induced IL-33 release, and prevented disruption of tight junction protein occludin in murine models. In vitro, TRPV1 antagonism suppressed capsaicin-induced calcium influx, NF-κB activation, and IL-33 overexpression.
CONCLUSIONS: Allergen exposure enhances the secretion of IL-33 in hNECs via the TRPV1-NF-κB pathway, thus compromising epithelial tight junction integrity. Inhibition of TRPV1 can attenuate the effects of allergen-induced innate nasal epithelial responses. Our study offers novel insights into the potential therapeutic targeting of TRPV1 in AR.

Keywords:  Allergic rhinitis; IL-33; NF-κB pathway; TRPV1; Tight junctions

DOI:  https://doi.org/10.1016/j.intimp.2025.114807
Elife. 2025 May 14. pii: RP102659. [Epub ahead of print]14

Reprogramming of GM-CSF-dependent alveolar macrophages through GSK3 activity modulation.

Israel Ríos, Cristina Herrero, Mónica Torres-Torresano, Baltasar López-Navarro, María Teresa Schiaffino, Francisco Díaz Crespo, Alicia Nieto-Valle, Rafael Samaniego, Yolanda Sierra-Palomares, Eduardo Oliver, Fernando Revuelta-Salgado, Ricardo García-Luján, Paloma Sánchez-Mateos, Rafael Delgado, Amaya Puig-Kröger, Angel L Corbí.

  Monocyte-derived macrophages recruited into inflamed tissues can acquire an array of functional states depending on the extracellular environment. Since the anti-inflammatory/pro-fibrotic macrophage profile is determined by MAFB, whose activity/protein levels are regulated by GSK3, we addressed the macrophage reprogramming potential of GSK3 modulation. GM-CSF-dependent (GM-MØ) and M-CSF-dependent monocyte-derived macrophages (M-MØ) exhibited distinct levels of inactive GSK3, and inhibiting GSK3 in GM-MØ led to the acquisition of transcriptional, phenotypic, and functional properties characteristic of M-MØ (enhanced expression of IL-10 and monocyte-recruiting factors, and higher efferocytosis). These reprogramming effects were also observed upon GSK3α/β knockdown and through GSK3 inhibition in ex vivo isolated human alveolar macrophages (AMØ). Notably, GSK3 downmodulation potentiated the transcriptional signature of interstitial macrophages (IMØ) while suppressing the AMØ-specific gene profile. Indeed, heightened levels of inactive GSK3 and MAFB-dependent proteins were observed in severe COVID-19 patients' lung macrophages, highlighting the GSK3-MAFB axis as a therapeutic target for macrophage reprogramming.

Keywords:  GSK3; human; immunology; inflammation; macrophage reprogramming; macrophages

DOI:  https://doi.org/10.7554/eLife.102659
Proc Natl Acad Sci U S A. 2025 May 20. 122(20): e2412447122

Staphylococcus aureus SaeR/S-regulated factors overcome human complement-mediated inhibition of aggregation to evade neutrophil killing.

Brian A Pettygrove, Tyler K Nygaard, Timothy R Borgogna, Natalia Malachowa, Gauri Gaur, Shannon E Salo, Kyler B Pallister, Owen Burroughs, Cassandra Robinson, Annika Gao, Daniel E Sturdevant, Stacy Ricklefs, Frank R DeLeo, Michael Otto, Philip S Stewart, Jovanka M Voyich.

  Staphylococcus aureus (S. aureus) is a frequent culprit in implant-associated infections and employs many virulence factors to escape killing by the host immune system. The specific immune evasion strategies used by small aggregates of S. aureus on a surface, precursors to mature biofilm, are still relatively unknown. Time-lapse confocal microscopy was leveraged to quantify interactions between S. aureus aggregates and human neutrophils in vitro and identify specific mechanisms of resistance to neutrophil killing. Surface-associated wild-type S. aureus rapidly formed small biofilm aggregates when grown in human serum. Conversely, aggregation was inhibited when the SaeR/S two-component gene regulatory system was deleted. Wild-type aggregates began to show individual and population-level resistance to neutrophil killing upon reaching sizes of approximately 50 to 75 µm2, whereas Δsae clusters failed to reach these sizes and were readily cleared. Aggregation of Δsae strains was impaired by serum complement, and this inhibition required complement proteins C3 and factor B, but not C4 or C5, suggesting that this activity primarily occurs at the level of the alternative pathway. Several complement-inhibiting genes regulated by SaeR/S were identified that collectively facilitate biofilm aggregate formation in human, but not murine serum. Finally, aggregation of two related opportunistic pathogens, Staphylococcus epidermidis and Enterococcus faecalis, was inhibited by serum. These data demonstrate a function of serum complement, the ability to inhibit bacterial aggregation, that is potently blocked by S. aureus through the production of multiple complement-interfering proteins that are regulated by the SaeR/S system.

Keywords:  Staphylococcus aureus; biofilm; complement; microscopy; neutrophil

DOI:  https://doi.org/10.1073/pnas.2412447122
Diagnostics (Basel). 2025 Apr 25. pii: 1090. [Epub ahead of print]15(9):

Hallmarks of Bacterial Vaginosis.

Diana Cristina Pérez-Ibave, Carlos Horacio Burciaga-Flores, Ximena García-Mejía, Fernando Alcorta-Nuñez, Orlando Solis-Coronado, Moisés González Escamilla, Oscar Vidal-Gutiérrez, María Lourdes Garza-Rodríguez.

  Background: Bacterial vaginosis (BV) is considered the most common cause of vaginal discharge, which is related to several public health issues, such as an increased risk for sexually transmitted infections, pelvic inflammatory disease, pregnancy-related problems such as abortion, stillbirth or premature birth, and tubal factor infertility. BV is not considered an infection but an imbalance in the vaginal microbiota, characterized by a substitution of the normal Lactobacilli flora by anaerobe. Reducing resistance against infections by several mechanisms, including bacterial homeostasis, stabilization of acid pH, inhibition of pathogens adhesion by polyamine degradation, production of anti-inflammatory molecules, surfactants, and antimicrobial substances like hydrogen peroxide, acids, and bacteriocins. Approximately half of women with BV can experience symptoms, which mainly include vaginal malodor, fishy discharge, stinging sensation, and increased vaginal pH. The treatment of BV is based primarily on promoting Lactobacilli restoration and eliminating dangerous microbiota with antibiotic therapy. However, there is a high rate of recurrence and relapse. Objective: Based on the current literature, this review aims to propose a list of ten BV hallmarks: dysbiosis, inflammation, apoptosis, pH basification, mucosal barrier integrity, pathway activation, epithelial damage, genomic instability, oxidative stress (OS), and metabolic reconfiguration. Conclusions: Understanding the causes of BV and the pathogenicity mechanisms is critical for preventing and improving the current therapeutic management of patients.

Keywords:  Gardnerella vaginalis; Lactobacillus; bacterial vaginosis; dysbiosis; hallmarks; vaginal epithelial damage; vaginal microbiota

DOI:  https://doi.org/10.3390/diagnostics15091090
Respir Res. 2025 May 10. 26(1): 181

SERPINB10 promotes macrophage M2 polarization and airway inflammation in asthma.

Lu Zhao, Wenliang Wu, Gongqi Chen, Chunli Huang, Weiqiang Kong, Wei Gu, Huiru Jie, Lingling Yi, Guohua Zhen.

   BACKGROUND: Macrophage M2 polarization plays a critical role in type 2 airway inflammation in asthma. We previously reported that serine peptidase inhibitor, clade B, member 10 (SERPINB10) promotes airway eosinophilic inflammation in asthma.
OBJECTIVE: To investigate the role of SERPINB10 in macrophage M2 polarization and airway inflammation in asthma.
METHODS: The expression of SERPINB10 was detected in bronchoalveolar lavage (BAL) cells from 15 control subjects and 36 asthma patients. Serpinb10 knockout mice and wild type mice were sensitized and challenged with ovalbumin (OVA). Macrophage polarization and airway inflammation were evaluated. An adoptive transfer experiment of Serpinb10-deficient macrophages to macrophage-depleted mice was performed to assess the effect of Serpinb10 deficiency in macrophages on the airway inflammation in the model. The role of SERPINB10 in the activation of IL-4 receptor (IL-4R) signaling pathway and macrophage M2 polarization was investigated in cell cultures.
RESULTS: SERPINB10 expression was markedly elevated in BAL cells from asthmatic patients, and was significantly correlated with fractional exhaled nitric oxide and CD206, a marker for macrophage M2 polarization. In the OVA-induced allergic airway inflammation mouse model, Serpinb10 deficiency significantly inhibited airway inflammation, mucous cell metaplasia and airway hyperresponsiveness. Moreover, Serpinb10 deficiency suppressed the expression of M2 markers including Cd206, Arg1 in mouse lung tissues and the protein levels of M2 macrophage effector cytokines including Ccl17 and Ccl22 in BAL fluid. Adoptive transfer of Serpinb10-deficient bone marrow-derived macrophages (BMDMs) to wild type mice depleted macrophages significantly suppressed the airway inflammation and mucous cell metaplasia. Mechanistically, SERPINB10 suppresses the degradation of IL-4Rα in macrophages, thereby upregulating the phosphorylation of Stat6 and Akt and leading to macrophage M2 polarization.
CONCLUSIONS: SERPINB10 promotes macrophage M2 polarization by suppressing IL-4Rα degradation and upregulating IL-4R signaling. SERPINB10 is a potential therapeutic target for asthma.

Keywords:  Airway inflammation; Asthma; IL-4Rα; Macrophage polarization; SERPINB10

DOI:  https://doi.org/10.1186/s12931-025-03252-3
Acta Pharmacol Sin. 2025 May 14.

GPR40 activation alleviates pulmonary fibrosis by repressing M2 macrophage polarization through the PKD1/CD36/TGF-β1 pathway.

Hui-Qi Wan, Ling-Feng Xie, Hong-Lin Li, Yan Ma, Qiu-Hui Li, Meng-Qing Dai, Yuan-Dong Fu, Wen-Jun Li, Jin-Pei Zhou, Min-Yi Qian, Xu Shen.

  Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by complex aetiologies involving the accumulation of inflammatory cells, such as macrophages, in the alveoli. This process is driven by uncontrolled extracellular matrix (ECM) deposition and the development of fibrous connective tissues. Here, we observed that the mRNA expression of Ffar1, the gene encoding G protein-coupled receptor 40 (GPR40), is repressed, while Cd36 is increased in the bronchoalveolar lavage fluid (BALF), which is predominantly composed of alveolar macrophages, of IPF patients. Furthermore, the GPR40 protein was found to be largely adhered to macrophages and was pathologically downregulated in the lungs of bleomycin (BLM)-induced PF model mice (PF mice) compared with those of control mice. Specific knockdown of GPR40 in pulmonary macrophages by adeno-associated virus 9-F4/80-shGPR40 (AAV9-shGPR40) exacerbated the fibrotic phenotype in the PF mice, and activation of GPR40 by its determined agonist compound SC (1,3-dihydroxy-8-methoxy-9H-xanthen-9-one) effectively protected the PF mice from pathological exacerbation. Moreover, Ffar1 or Cd36 gene knockout mouse-based assays were performed to explore the mechanism underlying the regulation of GPR40 activation in pulmonary macrophages with compound SC as a probe. We found that compound SC mitigated pulmonary fibrosis progression by preventing M2 macrophage polarization from exerting profibrotic effects through the GPR40/PKD1/CD36 axis. Our results strongly support the therapeutic potential of targeting intrinsic GPR40 activation in pulmonary macrophages for IPF and highlight the potential of compound SC in treating this disease.

Keywords:  GPR40; GPR40/PKD1/CD36 axis; M2 macrophage; pulmonary fibrosis

DOI:  https://doi.org/10.1038/s41401-025-01558-y
Trends Mol Med. 2025 May 06. pii: S1471-4914(25)00087-5. [Epub ahead of print]

New insights into gut microbiota-prostate cancer crosstalk.

Jalal Laaraj, Gabriel Lachance, Alain Bergeron, Yves Fradet, Karine Robitaille, Vincent Fradet.

  Recent evidence underscores a reciprocal relationship between the gut microbiota and prostate cancer (PCa). Dysbiosis, often driven by Western dietary habits and antibiotic use, can heighten systemic inflammation and hinder antitumor immunity, thereby fostering PCa onset and progression. Conversely, certain gut microbes and their metabolites may protect against tumor growth by modulating immune and hormonal pathways that impact therapeutic responses, including androgen deprivation therapy (ADT). Emerging evidence links gut microbial shifts to PCa aggressiveness, potentially sustaining local androgen production and promoting resistance. In this review, we explore current understanding of the gut-PCa interplay, highlighting key knowledge gaps and the need for further research to clarify how targeting the microbiome might influence PCa outcomes.

Keywords:  Western dietary habits; dysbiosis; gut microbiota,; gut-derived metabolites; immunotherapy; prostate cancer

DOI:  https://doi.org/10.1016/j.molmed.2025.03.015
Glob Chall. 2025 May;9(5): 2400302

Occupationally Relevant Zinc- and Copper-Containing Metal Fumes Inhibit Human THP-1 Macrophage TNF and IL-6 Responses to Bacterial Stimuli.

Jan Steffens, Sabrina Michael, Katharina Kuth, Henner Hollert, Miriam Du Marchie Sarvaas, Andrijana Nesic, Thomas Kraus, Ralf Baumann.

  Metal workers have an increased risk of severe lobar pneumonia due to exposure to metal fume particles, which lead to recent pneumococcal vaccination recommendations. To investigate the effects of metal fume-derived zinc oxide (ZnO) and copper oxide (CuO) particles on airway immune responses, human THP-1-derived macrophages are exposed in vitro to the bacterial pathogen-associated molecular patterns (PAMPs) lipopolysaccharide (LPS), lipoteichoic Acid (LTA), or peptidoglycan (PGN), together with particle suspensions. Particles are generated through metal inert gas (MIG) soldering. Spectrometric and microscopic analysis confirms CuO and ZnO as main components. Macrophage IL-6 and TNF mRNAs are quantified by qPCR and secreted protein levels by electrochemiluminescent multi-spot assay. A dose-dependent increase in macrophage TNF and IL-6 mRNA (4 h) and protein (24 h) levels following exposure to PAMPs is significantly inhibited by 2 µg mL-1 CuO/ZnO particles (n = 5). Additionally, CuO/ZnO particles significantly inhibit TNF protein expression in unstimulated macrophages, while IL-6 protein levels are unaffected (n = 5). The presented in vitro immunotoxicity approach may extend existing new approach methodology (NAM) elements for chemical risk assessment and possibly exposure limit evaluation refinements. These findings implicate that CuO/ZnO particles suppress macrophage proinflammatory responses to PAMPs, potentially compromising lung immunity, underlining current vaccine recommendations and efforts for preventive occupational health guidelines.

Keywords:  CuO/ZnO particles; immunosuppressive effects on macrophages; metal (nano)‐particle exposure; welding and metal fumes; workplace safety and new approach methodologies (NAM)

DOI:  https://doi.org/10.1002/gch2.202400302