bims-bac4me 2025-02-02 papers

bims-bac4me

Biomed News

on Microbiome and trained immunity

Issue of 2025–02–02
forty-one papers selected by
Chun-Chi Chang, Universitäts Spital Zürich

Advancing veterinary vaccines design through trained immunity insights.
SLAMF8 Disrupts Epithelial Barrier in Chronic Rhinosinusitis with Nasal Polyps via M1 Macrophage Polarization.
Species- and strain-specific microbial modulation of interferon, innate immunity, and epithelial barrier in 2D air-liquid interface respiratory epithelial cultures.
MCT1 lactate transporter blockade re-invigorates anti-tumor immunity through metabolic rewiring of dendritic cells in melanoma.
Strategies for Survival of Staphylococcus aureus in Host Cells.
Innate Immunity Never "NODs" Off: NLRs Regulate the Host Anti-Viral Immune Response.
Type I Interferon Targets Alveolar Macrophages to Promote Bacterial Pneumonia after Viral Infection.
Schistosoma mansoni antigen induced innate immune memory features mitochondrial biogenesis and can be inhibited by ovarian produced hormones.
Role of nasal microbiota in regulating host anti-influenza immunity in dogs.
Lifelong partners: Gut microbiota-immune cell interactions from infancy to old age.
Arginine metabolism in myeloid cells in health and disease.
Sorting Out the SOCS Genes and Their Role in Macrophage Activation.
Underground bacteria serve alcohol to methane-making microbes.
Enter the Matrix: Fibroblast-immune cell interactions shape extracellular matrix deposition in health and disease.
Genetic variation in IL-4 activated tissue resident macrophages determines strain-specific synergistic responses to LPS epigenetically.
The Role of Dectin-1-Akt-RNF146 Pathway in β-Glucan Induced Immune Trained State of Monocyte in Sepsis.
PANoptosis in Bacterial Infections: A Double-Edged Sword Balancing Host Immunity and Pathogenesis.
Carbon monoxide alleviates endotoxin-induced acute lung injury via NADPH oxidase inhibition in macrophages and neutrophils.
TIR signaling activates caspase-like immunity in bacteria.
Role of inflammasomes in acute respiratory distress syndrome.
Staphylococcus aureus vesicles impair cutaneous wound healing through p38 MAPK-MerTK cleavage-mediated inhibition of macrophage efferocytosis.
The Importance of Lung Innate Immunity During Health and Disease.
Single-cell profiling of the immune landscape across the human lifespan.
Guards and decoys: RIPoptosome and inflammasome pathway regulators of bacterial effector-triggered immunity.
From Cure to Crisis: Understanding the Evolution of Antibiotic-Resistant Bacteria in Human Microbiota.
CEACAM5 exacerbates asthma by inducing ferroptosis and autophagy in airway epithelial cells through the JAK/STAT6-dependent pathway.
Developing human upper, lower, and deep lung airway models: Combining different scaffolds and developing complex co-cultures.
Mycobacteria Exploit Host GPR84 to Dampen Pro-Inflammatory Responses and Promote Infection in Macrophages.
NTHi killing activity is reduced in COPD patients and is associated with a differential microbiome.
Intestinal Epithelial Ptpn23 Is Essential For Gut Barrier Integrity And Prevention Of Fatal Bacterial Translocation.
Countering antimicrobial resistance.
Single-Cell Landscape of Bronchoalveolar Lavage Fluid Identifies Specific Neutrophils during Septic Immunosuppression.
Physiologically Relevant Coculture Model for Oral Microbial-Host Interactions.
Sepsis-induced NET formation requires MYD88 but is independent of GSDMD and PAD4.
Heterogeneity in preoperative Staphylococcus aureus screening and decolonization strategies among healthcare institutions.
Histone lactylation regulates PRKN-Mediated mitophagy to promote M2 Macrophage polarization in bladder cancer.
DSCI: a database of synthetic biology components for innate immunity and cell engineering decision-making processes.
Monocytes and interstitial macrophages contribute to hypoxic pulmonary hypertension.
Evidence that staphylococcal superantigens promote within-patient bacterial persistence following post-operative surgical site infection.
HMGB1-mediated CIITA super-enhancers are critical for DC trained immunity in acute-to-chronic progression of allograft rejection.
Multifaceted interplays between the essential players and lipid peroxidation in ferroptosis.

Front Vet Sci. 2024 ;11 1524668

Advancing veterinary vaccines design through trained immunity insights.

Xin Wang, Guohua Yu.

  Trained immunity, characterized by long-term functional reprogramming of innate immune cells, offers promising new directions for veterinary vaccine development. This perspective examines how trained immunity can be integrated into veterinary vaccine design through metabolic reprogramming and epigenetic modifications. We analyze key molecular mechanisms, including the shift to aerobic glycolysis and sustained epigenetic changes, that enable enhanced immune responses. Strategic approaches for vaccine optimization are proposed, focusing on selecting effective trained immunity inducers, developing innovative adjuvant systems, and achieving synergistic enhancement of immune responses. While implementation challenges exist, including individual response variations and safety considerations, trained immunity-based vaccines show potential for providing broader protection against emerging pathogens. This approach could revolutionize veterinary vaccinology by offering enhanced efficacy and cross-protection against heterologous infections, particularly valuable for zoonotic disease control.

Keywords:  epigenetic modification; innate immune memory; metabolic reprogramming; trained immunity; veterinary vaccines

DOI:  https://doi.org/10.3389/fvets.2024.1524668
Ann Allergy Asthma Immunol. 2025 Jan 25. pii: S1081-1206(25)00047-X. [Epub ahead of print]

SLAMF8 Disrupts Epithelial Barrier in Chronic Rhinosinusitis with Nasal Polyps via M1 Macrophage Polarization.

Danyang Li, Longgang Yu, Jiajia Zi, Xiaoyun Du, Xudong Yan, Han Chen, Lin Wang, Chunge Zheng, Guangyi Wang, Jisheng Zhang, Yan Jiang.

   BACKGROUND: Recent studies show that M1 macrophages accumulate predominantly in non-eosinophilic chronic rhinosinusitis with nasal polyps (neCRSwNP). However, the precise mechanisms regulating M1 macrophages and their impact on the epithelial barrier remain unclear.
OBJECTIVE: We aim to investigate the expression and regulatory role of SLAMF8, a molecule exclusively expressed in myeloid cells, in M1 macrophage polarization and its potential contribution to neCRSwNP development.
METHODS: We evaluated SLAMF8 expression and its correlation with clinical variables using real-time quantitative polymerase chain reaction and Western blot in sinonasal mucosa samples from CRSwNP and control subjects. Immunofluorescence staining confirmed the co-expression of SLAMF8 with macrophages. After SLAMF8 knockdown, we explored the influence on macrophage M1 polarization and the effect on epithelial-mesenchymal transition (EMT) process and tight junction integrity in epithelial cells through an indirect co-culture system of M1 macrophages with human nasal epithelial cells.
RESULTS: SLAMF8 was highly expressed on M1 macrophages in polyp tissues, notably in neCRSwNP, and correlated with disease severity indices only in neCRSwNP. SLAMF8 knockdown in THP-1 cells reduced M1 macrophage markers (CD86, iNOS, and NLRP3) and decreased secretion of inflammatory cytokines (IL-1β, IL-6, and TNF-α). Co-culture with M1 macrophage supernatant after SLAMF8 knockdown enhanced epithelial viability, reduced EMT and apoptosis, and upregulated tight junction markers Occludin and Claudin-4 in nasal epithelial cells.
CONCLUSION: SLAMF8 elevation correlates with the EMT, epithelial tight junction and disease severity in neCRSwNP. The SLAMF8 upregulation promotes M1 macrophage polarization, by which facilitates EMT and impairs nasal epithelial barrier function. SLAMF8 may represent a novel therapeutic target for neCRSwNP.

Keywords:  M1 polarization; chronic rhinosinusitis with nasal polyps; epithelial barrier; macrophages

DOI:  https://doi.org/10.1016/j.anai.2025.01.020
BMC Biol. 2025 Jan 29. 23(1): 28

Species- and strain-specific microbial modulation of interferon, innate immunity, and epithelial barrier in 2D air-liquid interface respiratory epithelial cultures.

Mian Horvath, Ruoyu Yang, Diana Cadena Castaneda, Megan Callender, Elizabeth S Aiken, Anita Y Voigt, Ryan Caldwell, José Fachi, Blanda Di Luccia, Zoe Scholar, Peter Yu, Andrew Salner, Marco Colonna, Karolina Palucka, Julia Oh.

   BACKGROUND: The microbiome regulates the respiratory epithelium's immunomodulatory functions. To explore how the microbiome's biodiversity affects microbe-epithelial interactions, we screened 58 phylogenetically diverse microbes for their transcriptomic effect on human primary bronchial air-liquid interface (ALI) cell cultures.
RESULTS: We found distinct species- and strain-level differences in host innate immunity and epithelial barrier response. Strikingly, we found that host interferon, an antiviral response, was one of the most variable host processes. This variability was not driven by microbial phylogenetic diversity, bioburden, nor by the microbe's ability to stimulate other innate immunity pathways.
CONCLUSIONS: Microbial colonization differentially stimulates host gene expression with variations observed across phylogenetically diverse microbes and across different strains of the same species. Our study provides a foundation for understanding how the respiratory microbiome's biodiversity affects epithelial, and particularly antiviral, innate immunity.

Keywords:  Antiviral immunity; Bacteria; Epithelium; Interferon; Phylogenetically diverse microbes; RNA-seq; Respiratory microbiome; Strain differences

DOI:  https://doi.org/10.1186/s12915-025-02129-7
Nat Commun. 2025 Jan 27. 16(1): 1083

MCT1 lactate transporter blockade re-invigorates anti-tumor immunity through metabolic rewiring of dendritic cells in melanoma.

Camille Niveau, Mélanie Cettour-Cave, Stéphane Mouret, Eleonora Sosa Cuevas, Mylene Pezet, Benoît Roubinet, Hugo Gil, Florence De Fraipont, Ludovic Landemarre, Julie Charles, Philippe Saas, Caroline Aspord.

Dendritic cells (DC) are key players in antitumor immune responses. Tumors exploit their plasticity to escape immune control; their aberrant surface carbohydrate patterns (e.g., glycans) shape immune responses through lectin binding, and manipulate the metabolism of immune cells, including DCs to alter their function and escape immune surveillance. DC metabolic reprogramming could induce immune subversion and tumor immune escape. Here we explore metabolic features of human DC subsets (cDC2s, cDC1s, pDCs) in melanoma, at single cell level, using the flow cytometry-based SCENITH (Single-Cell ENergetIc metabolism by profiling Translation inHibition) method. We demonstrate that circulating and tumor-infiltrating DC subsets from melanoma patients are characterized by altered metabolism, which is linked to their activation status and profile of immune checkpoint expression. This altered metabolism influences their function and affects patient clinical outcome. Notably, melanoma tumor cells directly remodel the metabolic profile of DC subsets, in a glycan-dependent manner. Strikingly, modulation of the mTOR/AMPK-dependent metabolic pathways and/or the MCT1 lactate transporter rescue cDC2s and cDC1s from skewing by tumor-derived glycans, Sialyl-Tn antigen and Fucose, and restore anti-tumor T-cell fitness. Our findings thus open the way for appropriate tuning of metabolic pathways to rescue DCs from tumor hijacking and restore potent antitumor responses.

DOI: https://doi.org/10.1038/s41467-025-56392-x
Int J Mol Sci. 2025 Jan 16. pii: 720. [Epub ahead of print]26(2):

Strategies for Survival of Staphylococcus aureus in Host Cells.

Huiling Xu, Shengnan Wang, Xiaoting Liu, Muzi Li, Xiaozhou Wang, Huahua Chen, Chaonan Qu, Yongxia Liu, Jianzhu Liu.

  Staphylococcus aureus, a common pathogen, is capable of producing a significant array of toxins and can develop biofilms or small colony variants (SCVs) to evade detection by the immune system and resist the effects of antibiotics. Its ability to persist for extended periods within host cells has led to increased research interest. This review examines the process of internalization of S. aureus, highlighting the impact of its toxins and adhesion factors on host cells. It elucidates the intricate interactions between them and the host cellular environment, thereby offering potential strategies for the treatment and prevention of S. aureus infections.

Keywords:  EVs; SCVs; Staphylococcus aureus; biofilms; internalization; toxin

DOI:  https://doi.org/10.3390/ijms26020720
Immunol Rev. 2025 Mar;330(1): e13429

Innate Immunity Never "NODs" Off: NLRs Regulate the Host Anti-Viral Immune Response.

Mackenzie K Woolls, Madeline D Mott, Cassandra S Poole, Julia A Gregory, Hannah M Ivester, Irving Coy Allen.

  A robust innate immune response is essential in combating viral pathogens. However, it is equally critical to quell overzealous immune signaling to limit collateral damage and enable inflammation resolution. Pattern recognition receptors are critical regulators of these processes. The cytosolic nucleotide-binding domain leucine-rich repeat (NLR; NOD-like receptor) family of pattern recognition receptors plays essential roles in the sensing of viral pathogen-associated molecular patterns and is best characterized for itsr pro-inflammatory biological functions. Specifically, these include the formation of multi-protein complexes, defined as inflammasomes or NODosomes that regulate the production of IL-1beta, IL-18, and pyroptosis, or the induction of NF-ΚB signaling. While these biological effects are inherently pro-inflammatory, it is also important to recognize that other NLR family members conversely function to negatively regulate inflammation through modulating signaling initiated by other families of pattern recognition receptors. Mechanistically, these unique NLRs also form multiprotein complexes that act to attenuate a variety of biological signaling pathways, such as the inhibition of NF-ΚB. This inhibition facilitates inflammation resolution and functions to restore cellular homeostasis. Despite extensive characterization of individual NLR family members, the mechanisms of immune system regulation are highly nuanced and remain enigmatic. This is especially true for non-inflammasome-forming, regulatory NLRs. Here, we discuss recent findings associated with NLR family members that play essential roles in the host immune response to viruses and mechanisms by which these pattern recognition receptors may function to regulate antiviral immunity.

Keywords:  NOD‐like receptors; antiviral immunity; inflammasome; inflammation; virus

DOI:  https://doi.org/10.1111/imr.13429
Am J Respir Cell Mol Biol. 2025 Jan 29.

Type I Interferon Targets Alveolar Macrophages to Promote Bacterial Pneumonia after Viral Infection.

Sunil Palani, Md Bashir Uddin, Michael McKelvey, Shengjun Shao, Wenzhe Wu, Xiaoyong Bao, Jiaren Sun, Keer Sun.

  Exposure to influenza A virus (IAV), respiratory syncytial virus (RSV), and human metapneumovirus (hMPV) is well-known to increase the risk of Streptococcus pneumoniae (SPn) pneumonia in humans. Type I interferon (IFN-I) is a hallmark response to acute viral infections, and alveolar macrophages (AMs) constitute the first line of airway defense against opportunistic bacteria. Our study reveals that virus-induced IFN-I receptor (IFNAR1) signaling directly impairs AM-dependent antibacterial protection. Using Ifnar1 conditional knockout mouse models, in vivo antibodies, bone marrow chimeric mice, and AM reconstitution, we demonstrate that IFN-I intrinsically targets AMs to drive hypersusceptibility to SPn following IAV infection. Importantly, we show that RSV and hMPV infection induces robust IFN-I signaling in AMs, coinciding with lethal susceptibility to secondary SPn pneumonia. In contrast, seasonal human coronavirus neither induces significant IFN-I signaling in AMs nor immune predisposition to SPn. Therefore, we conclude that IFN-I inhibition of AMs represents a crucial mechanism underlying antibacterial complications following otherwise asymptomatic or mild respiratory viral infections.

Keywords:  Influenza; RSV; S. pneumoniae; co-infection

DOI:  https://doi.org/10.1165/rcmb.2024-0552OC
bioRxiv. 2025 Jan 18. pii: 2025.01.14.632838. [Epub ahead of print]

Schistosoma mansoni antigen induced innate immune memory features mitochondrial biogenesis and can be inhibited by ovarian produced hormones.

Juan Marcos Oviedo, Diana Cortes-Selva, Marco Marchetti, Lauren Gordon, Lisa Gibbs, J Alan Maschek, James Cox, Seth Frietze, Eyal Amiel, Keke C Fairfax.

  We have previously identified that S. mansoni infection induces a unique form of myeloid training that protects male but not female mice from high fat diet induced disease. Here we demonstrate that ovarian derived hormones account for this sex specific difference. Ovariectomy of females prior to infection permits metabolic reprogramming of the myeloid lineage, with BMDM exhibiting carbon source flexibility for cellular respiration, and mice protected from systemic metabolic disease. The innate training phenotype of infection can be replicated by in vivo injection of SEA, and by exposure of bone marrow to SEA in culture prior to macrophage differentiation (Day 0). This protective phenotype is linked to increased chromatin accessibility of lipid and mitochondrial pathways in BMDM including Nrf1 and Tfam, as well as mitochondrial biogenesis. This work provides evidence that S. mansoni antigens induce a unique form of innate training inhibited by ovarian-derived hormones in females.

Keywords:  Myeloid lineage; Schistosoma mansoni; biological sex; innate training; macrophage metabolism; metabolic disease

DOI:  https://doi.org/10.1101/2025.01.14.632838
Microbiome. 2025 Jan 27. 13(1): 27

Role of nasal microbiota in regulating host anti-influenza immunity in dogs.

Jinzhu Geng, Yuhao Dong, Hao Huang, Xia Wen, Ting Xu, Yanbing Zhao, Yongjie Liu.

   BACKGROUND: Numerous studies have confirmed a close relationship between the pathogenicity of influenza and respiratory microbiota, but the mechanistic basis for this is poorly defined. Also, the majority of these studies have been conducted on murine models, and it remains unclear how far these findings can be extrapolated from murine models to other animals. Considering that influenza A virus is increasingly recognized as an important canine respiratory pathogen, this study investigated the cross-talk between nasal and lung tissues mediated by microbes and its association with influenza susceptibility in a beagle dog model.
RESULTS: Using 16S rRNA gene sequencing, combined with comparative transcriptomic, anatomical, and histological examinations, we investigated viral presence, gene expression profiles, and microbiota in the nasal cavity and lung after influenza infection in the beagles with antibiotic-induced nasal dysbiosis. Our data showed that dysbiosis of the nasal microbiome exacerbates influenza-induced respiratory disease and the epithelial barrier disruption, and impairs host antiviral responses in the nasal cavity and lung. Moreover, dysregulation of nasal microbiota exacerbates the influenza-induced disturbance in lung microbiota. Further, we also identified a strain of Lactobacillus plantarum isolated from canine nasal cavity with a significant antiviral effect in vitro, and found that its antiviral activity might be associated with the activation of the interferon (IFN) pathway and modulation of the impaired autophagy flux induced by influenza infection.
CONCLUSIONS: Our investigation reveals that nasal microbiota dysbiosis exerts a prominent impact on host antiviral responses, inflammation thresholds, and mucosal barrier integrity during influenza infection. Lactobacilli, as part of the nasal microbiota, may contribute to host antiviral defenses by modulating the IFN and autophagy pathways. Collectively, this study underscores the importance of nasal microbiota homeostasis in maintaining respiratory health. Video Abstract.

Keywords:  Autophagy; IFN; Influenza; Respiratory microbiome

DOI:  https://doi.org/10.1186/s40168-025-02031-y
Mucosal Immunol. 2025 Jan 23. pii: S1933-0219(25)00006-6. [Epub ahead of print]

Lifelong partners: Gut microbiota-immune cell interactions from infancy to old age.

Julia A Brown, Hilal Bashir, Melody Y Zeng.

Our immune system and gut microbiota are intricately coupled from birth, both going through maturation during early life and senescence during aging almost in a synchronized fashion. The symbiotic relationship between the human host and microbiota is critically dependent on a healthy immune system to keep our microbiota in check, while the microbiota provides essential functions to promote the development and fitness of our immune system. The partnership between our immune system and microbiota is particularly important during early life, when microbial ligands and metabolites shape the development of the immune cells and immune tolerance; during aging, having sufficient beneficial gut bacteria is critical for the maintenance of intact mucosal barriers, immune metabolic fitness, and strong immunity against pathogens. The immune system during childhood is programmed, with the support of the microbiota, to develop robust immune tolerance, and limit autoimmunity and metabolic dysregulation, which are prevalent during aging. This review comprehensively explores the mechanistic underpinnings of gut microbiota-immune cell interactions during infancy and old age, with the goal to gain a better understanding of potential strategies to leverage the gut microbiota to combat age-related immune decline.

DOI: https://doi.org/10.1016/j.mucimm.2025.01.006
Semin Immunopathol. 2025 Jan 25. 47(1): 11

Arginine metabolism in myeloid cells in health and disease.

Eleftheria Karadima, Triantafyllos Chavakis, Vasileia Ismini Alexaki.

  Metabolic flexibility is key for the function of myeloid cells. Arginine metabolism is integral to the regulation of myeloid cell responses. Nitric oxide (NO) production from arginine is vital for the antimicrobial and pro-inflammatory responses. Conversely, the arginase 1 (ARG1)-dependent switch between the branch of NO production and polyamine synthesis downregulates inflammation and promotes recovery of tissue homeostasis. Creatine metabolism is key for energy supply and proline metabolism is required for collagen synthesis. Myeloid ARG1 also regulates extracellular arginine availability and T cell responses in parasitic diseases and cancer. Cancer, surgery, sepsis and persistent inflammation in chronic inflammatory diseases, such as neuroinflammatory diseases or arthritis, are associated with dysregulation of arginine metabolism in myeloid cells. Here, we review current knowledge on arginine metabolism in different myeloid cell types, such as macrophages, neutrophils, microglia, osteoclasts, tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs) and myeloid-derived suppressor cells (MDSCs). A deeper understanding of the function of arginine metabolism in myeloid cells will improve our knowledge on the pathology of several diseases and may set the platform for novel therapeutic applications.

Keywords:  Arginine metabolism; Cancer; Infection; Inflammation; Myeloid cells; Sepsis-induced immune paralysis; Surgery

DOI:  https://doi.org/10.1007/s00281-025-01038-9
J Interferon Cytokine Res. 2025 Jan 27.

Sorting Out the SOCS Genes and Their Role in Macrophage Activation.

Raymond P Donnelly.

  The suppressors of cytokine signaling (SOCS) genes were first described in a group of articles published in 1997. Since that time, much has been learned about the functional activities mediated by the corresponding proteins encoded by the SOCS genes. The SOCS gene family contains eight members: SOCS1 through SOCS7 and a highly related gene known as CISH (cytokine-inducible SH2-containing protein). Although much is known about the ability of the SOCS proteins to autoregulate responses to individual cytokines, much less is known about the ability of the SOCS proteins to cross-regulate cytokine signaling. The studies described in a new report by Bidgood et al. in this issue of JICR demonstrate that SOCS1 expression induced by one cytokine, interferon (IFN)-γ, can cross-regulate signaling induced by another cytokine, granulocyte macrophage colony-stimulating factor (GM-CSF), in murine bone marrow-derived macrophages. The authors show that the ability of SOCS1 to inhibit cytokine signaling is dose- and time-dependent. SOCS1 must reach a critical threshold level before it can exert a marked inhibitory effect on autocrine signaling through the IFN-γ receptor or paracrine signaling through the GM-CSF receptor.

Keywords:  GM-CSF; SOCS1; STAT1; interferon-γ; macrophages; signal transduction

DOI:  https://doi.org/10.1089/jir.2025.0016
Nature. 2025 Jan 29.

Underground bacteria serve alcohol to methane-making microbes.



Keywords:  Metabolism; Microbiology

DOI:  https://doi.org/10.1038/d41586-025-00199-9
F1000Res. 2024 ;13 119

Enter the Matrix: Fibroblast-immune cell interactions shape extracellular matrix deposition in health and disease.

Anthony Altieri, Grace V Visser, Matthew B Buechler.

  Fibroblasts, non-hematopoietic cells of mesenchymal origin, are tissue architects which regulate the topography of tissues, dictate tissue resident cell types, and drive fibrotic disease. Fibroblasts regulate the composition of the extracellular matrix (ECM), a 3-dimensional network of macromolecules that comprise the acellular milieu of tissues. Fibroblasts can directly and indirectly regulate immune responses by secreting ECM and ECM-bound molecules to shape tissue structure and influence organ function. In this review, we will highlight recent studies which elucidate the mechanisms by which fibroblast-derived ECM factors (e.g., collagens, fibrillar proteins) regulate ECM architecture and subsequent immune responses, with a focus on macrophages. As examples of fibroblast-derived ECM proteins, we examine Collagen Triple Helix Repeat Containing 1 (CTHRC1) and Transforming Growth Factor-β-inducible protein (TGFBI), also known as BIGH3. We address the need for investigation into how diverse fibroblast populations coordinate immune responses by modulating ECM, including the fibroblast-ECM-immune axis and the precise molecular mediators and pathways which regulate these processes. Finally, we will outline how novel research identifying key regulators of ECM deposition is critical for therapeutic development for fibrotic diseases and cancer.

Keywords:  BigH3; Cthrc1; Extracellular Matrix (ECM); Fibroblast heterogeneity; Fibroblasts; Immunology; Macrophages

DOI:  https://doi.org/10.12688/f1000research.143506.2
Nat Commun. 2025 Jan 25. 16(1): 1030

Genetic variation in IL-4 activated tissue resident macrophages determines strain-specific synergistic responses to LPS epigenetically.

Mingming Zhao, Dragana Jankovic, Verena M Link, Camila Oliveira Silva Souza, Katherine M Hornick, Oyebola Oyesola, Yasmine Belkaid, Justin Lack, Png Loke.

How macrophages in the tissue environment integrate multiple stimuli depends on the genetic background of the host, but this is still poorly understood. We investigate IL-4 activation of male C57BL/6 and BALB/c strain specific in vivo tissue-resident macrophages (TRMs) from the peritoneal cavity. C57BL/6 TRMs are more transcriptionally responsive to IL-4 stimulation, with induced genes associated with more super enhancers, induced enhancers, and topologically associating domains (TAD) boundaries. IL-4-directed epigenomic remodeling reveals C57BL/6 specific enrichment of NF-κB, IRF, and STAT motifs. Additionally, IL-4-activated C57BL/6 TRMs demonstrate an augmented synergistic response upon in vitro lipopolysaccharide (LPS) exposure, despite naïve BALB/c TRMs displaying a more robust transcriptional response to LPS. Single-cell RNA sequencing (scRNA-seq) analysis of mixed bone marrow chimeras indicates that transcriptional differences and synergy are cell intrinsic within the same tissue environment. Hence, genetic variation alters IL-4-induced cell intrinsic epigenetic reprogramming resulting in strain specific synergistic responses to LPS exposure.

DOI: https://doi.org/10.1038/s41467-025-56379-8
J Inflamm Res. 2025 ;18 1147-1165

The Role of Dectin-1-Akt-RNF146 Pathway in β-Glucan Induced Immune Trained State of Monocyte in Sepsis.

Chenyue Guo, Peiyao Xu, Wenchen Luo, Jinlin Zhang, Xingfeng Sun, Harry Hoang, Duan Ma, Dehua Wu, Jing Zhong, Changhong Miao.

   Background: Sepsis is regarded as a dysregulated immune response to infections. Recent study showed partially reversal of immunosuppression by trained immunity, which fosters an enhanced immune response towards a secondary challenge. However, the role of trained immunity in sepsis has not been fully understood.
Methods: We profiled the characteristics of peripheral blood mononuclear cells from septic patients using single-cell RNA sequencing (scRNA-seq) analyses. Murine double-hit models (pretreatment or post-treatment of β-glucan in septic mice) and murine monocyte/macrophage cell line RAW264.7 were used then.
Results: scRNA-seq revealed that Ring finger protein 146 (RNF146) and protein kinase B (Akt) were downregulated in the immunosuppression period of septic patients and were verified to be decreased in bone marrow and spleen monocytes from septic mice. While β-glucan pretreatment improved the immunosuppressed state in septic mice and increased dectin-1/Akt/RNF146 expressions in monocytes, along with the increased survival rate, inflammatory factors and aerobic glycolysis, indicating a change from immunosuppression to immune training. Moreover, RNF146 regulated dectin-1-Akt-mTOR signaling in the trained immune state of murine monocyte/macrophage RAW264.7 cell line and the expression of RNF146 was dependent on dectin-1-Akt activation. The inhibition of dectin-1 by its antagonist laminarin downregulated Akt-RNF146 signaling and partially reversed β-glucan induced trained immunity in septic mice.
Conclusion: RNF146 and Akt are downregulated in the immunosuppression period of sepsis, while increased after β-glucan pretreatment induced trained immunity in septic mice. Moreover, RNF146 regulates the immune trained state of monocyte through dectin-1-Akt-mTOR pathway, suggesting a possible target in reversal of immunosuppression in sepsis.

Keywords:  RNF146; immunosuppression; sepsis; trained immunity; β-glucan

DOI:  https://doi.org/10.2147/JIR.S482213
Pathogens. 2025 Jan 08. pii: 43. [Epub ahead of print]14(1):

PANoptosis in Bacterial Infections: A Double-Edged Sword Balancing Host Immunity and Pathogenesis.

Xiaoe He, Xiangyan Jiang, Jiayin Guo, Hui Sun, Jing Yang.

  PANoptosis is a newly identified programmed cell death pathway that integrates characteristics of apoptosis, pyroptosis, and necroptosis. It plays a dual role in the host immune response to bacterial infections. On one hand, PANoptosis acts as a protective mechanism by inducing the death of infected cells to eliminate pathogens and releasing pro-inflammatory cytokines to amplify the immune response. On the other hand, bacteria can exploit PANoptosis to evade host immune defenses. This dual nature underscores the potential of PANoptosis as a target for developing novel therapies against bacterial infections. This review summarizes the molecular mechanisms of PANoptosis, along with the crosstalk and integration of different cell death pathways in response to various bacterial pathogens. We also discuss the dual roles of PANoptosis in bacterial infectious diseases, including sepsis, pulmonary infections, and intestinal infections. Elucidating the molecular mechanisms underlying PANoptosis and how bacteria manipulate this pathway offers critical insights into host-pathogen interactions. These insights provide a foundation for designing targeted antibacterial strategies, modulating inflammation, and advancing precision medicine to improve clinical outcomes.

Keywords:  PANoptosis; bacterial infection; bacterial infectious disease; host–pathogen interactions; programmed cell death

DOI:  https://doi.org/10.3390/pathogens14010043
Biochem Pharmacol. 2025 Jan 27. pii: S0006-2952(25)00044-9. [Epub ahead of print]233 116782

Carbon monoxide alleviates endotoxin-induced acute lung injury via NADPH oxidase inhibition in macrophages and neutrophils.

Yuki Watabe, Victor Tuan Giam Chuang, Hiromi Sakai, Chihiro Ito, Yuki Enoki, Mitsutomo Kohno, Masaki Otagiri, Kazuaki Matsumoto, Kazuaki Taguchi.

  Sepsis is a life-threatening condition caused by severe infection and often complicates acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) due to the collapse of the oxidative and inflammatory balance induced by microbial pathogens, including lipopolysaccharides (LPS). In sepsis-related ARDS/ALI, NADPH oxidase (NOX) and toll-like receptors (TLR) in neutrophils and macrophages are key players in initiating oxidative and inflammatory imbalances. Although NOX and TLR activation has been linked to carbon monoxide (CO), the mechanism by which CO affects sepsis-related ARDS/ALI through NOX and TLR remains unknown. Here, we demonstrate that CO reduces sepsis-related ARDS/ALI by inhibiting NOX in neutrophils and macrophages, which in turn suppresses the production of reactive oxygen species (ROS), TLR4-associated inflammatory responses, and macrophage polarization toward M1-like macrophages. CO-bound hemoglobin vesicle (CO-HbV) therapy, a hemoglobin-based CO donor, exerts a protective effect against LPS-induced ALI by suppressing exaggerated oxidative and inflammatory responses and neutrophil and M1-like macrophage infiltration in the bronchoalveolar lavage fluid (BALF). Through suppression of NOX activity, CO decreased ROS generation, the TLR4/NF-κB signaling pathway, and macrophage polarization toward M1-like macrophages, according to cellular experiments conducted with peripheral neutrophils, BALF cells, and Raw264.7 cells. Moreover, ALI was found to be more severe in Hmox1+/- mice (mice with decreased endogenous CO production) than in the wild-type mice. Our findings suggest that both endogenously generated and exogenously supplied CO inhibit NOX-associated ROS generation, the TLR4/NF-κB signaling pathway, and macrophage polarization, thereby eliciting antioxidant and anti-inflammatory responses that prevent the onset and progression of LPS-induced ALI.

Keywords:  Acute lung injury; Carbon monoxide; Macrophage polarization; NADPH oxidase; Sepsis; Toll-like receptors

DOI:  https://doi.org/10.1016/j.bcp.2025.116782
Science. 2025 Jan 31. 387(6733): 510-516

TIR signaling activates caspase-like immunity in bacteria.

François Rousset, Ilya Osterman, Tali Scherf, Alla H Falkovich, Azita Leavitt, Gil Amitai, Sapir Shir, Sergey Malitsky, Maxim Itkin, Alon Savidor, Rotem Sorek.

Caspase family proteases and Toll/interleukin-1 receptor (TIR)-domain proteins have central roles in innate immunity and regulated cell death in humans. We describe a bacterial immune system comprising both a caspase-like protease and a TIR-domain protein. We found that the TIR protein, once it recognizes phage invasion, produces the previously unknown immune signaling molecule adenosine 5'-diphosphate-cyclo[N7:1'']-ribose (N7-cADPR). This molecule specifically activates the bacterial caspase-like protease, which then indiscriminately degrades cellular proteins to halt phage replication. The TIR-caspase defense system, which we denote as type IV Thoeris, is abundant in bacteria and efficiently protects against phage propagation. Our study highlights the diversity of TIR-produced immune signaling molecules and demonstrates that cell death regulated by proteases of the caspase family is an ancient mechanism of innate immunity.

DOI: https://doi.org/10.1126/science.adu2262
Thorax. 2025 Jan 30. pii: thorax-2024-222596. [Epub ahead of print]

Role of inflammasomes in acute respiratory distress syndrome.

Luke Flower, Emilio G Vozza, Clare E Bryant, Charlotte Summers.

  Acute respiratory distress syndrome (ARDS) is present in >10% of all people admitted to critical care and is associated with severe morbidity and mortality. Despite more than half a century since its first description, no efficacious pharmacological therapies have been developed, and little progress has been made in improving clinical outcomes. Neutrophils are the principal drivers of ARDS, with their priming and subsequent aberrant downstream functions, including interleukin (IL) 1β and IL-18 secretion, central to the disease pathogenesis. The dominant pathways through which IL-1β and IL-18 are believed to be elaborated are multimeric protein structures called inflammasomes that consist of sensor proteins, adaptor proteins and an effector enzyme. The inflammasome's initial activation depends on one of a variety of damage-associated (DAMP) or pathogen-associated (PAMP) molecular patterns. However, once activated, a common downstream inflammatory pathway is initiated regardless of the specific DAMP or PAMP involved. Several inflammasomes exist in humans. The nucleotide-binding domain leucine-rich repeat (NLR) family, pyrin domain-containing 3 (NLRP3), inflammasome is the best described in the context of ARDS and is known to be activated in both infective and sterile cases. The NLR family, caspase activation and recruitment domain-containing 4 (NLRC4) and absent in melanoma 2 (AIM2) inflammasomes have also been implicated in various ARDS settings, as have inflammasome-independent pathways. Further work is required to understand human biology as much of our knowledge is extrapolated from rodent experimental models. Experimental lung injury models have demonstrated beneficial responses to inflammasome, IL-1β and IL-18 blockade. However, findings have yet to be successfully translated into humans with ARDS, likely due to an underappreciation of the central role of the neutrophil inflammasome. A thorough understanding of inflammasome pathways is vital for critical care clinicians and researchers and for the development of beneficial therapies. In this review, we describe the central role of the inflammasome in the development of ARDS and its potential for immunomodulation, highlighting key areas for future research.

Keywords:  ARDS; Innate Immunity; Neutrophil Biology

DOI:  https://doi.org/10.1136/thorax-2024-222596
Cell Commun Signal. 2025 Jan 08. 23(1): 14

Staphylococcus aureus vesicles impair cutaneous wound healing through p38 MAPK-MerTK cleavage-mediated inhibition of macrophage efferocytosis.

Jiaxin Ou, Kangxin Li, Hui Yuan, Shaohua Du, Tingting Wang, Qiannan Deng, Huimei Wu, Weiyan Zeng, Kui Cheng, Kutty Selva Nandakumar.

   BACKGROUND: Staphylococcus aureus, a known contributor to non-healing wounds, releases vesicles (SAVs) that influence the delicate balance of host-pathogen interactions. Efferocytosis, a process by which macrophages clear apoptotic cells, plays a key role in successful wound healing. However, the precise impact of SAVs on wound repair and efferocytosis remains unknown.
METHODS: Filtration, ultracentrifugation, and iodixanol density gradient centrifugation were used to purify the bacterial vesicles. Transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot (WB) were used to characterize the vesicles. Macrophage efferocytosis efficiency was assessed using flow cytometry and confocal microscopy, while efferocytosis at wound sites was analyzed through WB, FACS, and TUNEL staining. Hematoxylin and eosin (H&E) staining and wound size measurements were used to evaluate the wound healing process. Phosphorylation of signaling pathways was detected by WB, and efferocytosis receptor expression was measured using RNA sequencing, qPCR, and flow cytometry. siRNA and pathway inhibitors were used to investigate the roles of key receptors and signaling pathways in efferocytosis.
RESULTS: We identified SAVs at infected wound sites, linking them to delayed healing of wounds. SAVs inhibit efferocytosis by activating the TLR2-MyD88-p38 MAPK signaling pathway, which regulates efferocytosis receptor genes. This activation promoted cleavage and shedding of MerTK, a crucial receptor for macrophage-driven efferocytosis. Notably, selective inhibition of p38 MAPK prevented MerTK shedding, restored efferocytosis and accelerated wound healing significantly, offering a promising therapeutic approach for chronic, non-healing wounds.
CONCLUSION: These findings uncover a novel mechanism in S. aureus-infected wounds, highlighting how the disruption of efferocytosis via the TLR2-MyD88-p38 MAPK-MerTK axis becomes a key force behind impaired healing of wounds. Targeting this pathway could open up a new therapeutic avenue facilitating the treatment of chronic, non-healing skin injuries.

Keywords:   Staphylococcus aureus ; Efferocytosis; Extracellular vesicles; MerTK; Wound healing

DOI:  https://doi.org/10.1186/s12964-024-01994-z
Pathogens. 2025 Jan 17. pii: 91. [Epub ahead of print]14(1):

The Importance of Lung Innate Immunity During Health and Disease.

Gusty Rizky Teguh Ryanto, Ratoe Suraya, Tatsuya Nagano.

  The lung is a vital organ for the body as the main source of oxygen input. Importantly, it is also an internal organ that has direct contact with the outside world. Innate immunity is a vital protective system in various organs, whereas, in the case of the lung, it helps maintain a healthy, functioning cellular and molecular environment and prevents any overt damage caused by pathogens or other inflammatory processes. Disturbances in lung innate immunity properties and processes, whether over-responsiveness of the process triggered by innate immunity or lack of responses due to dysfunctions in the immune cells that make up the innate immunity system of the lung, could be correlated to various pathological conditions. In this review, we discuss globally how the components of lung innate immunity are important not only for maintaining lung homeostasis but also during the pathophysiology of notable lung diseases beyond acute pulmonary infections, including chronic obstructive pulmonary disease (COPD), asthma, and pulmonary fibrosis.

Keywords:  COPD; asthma; lung infections; lung innate immunity; pulmonary fibrosis

DOI:  https://doi.org/10.3390/pathogens14010091
Nat Immunol. 2025 Feb;26(2): 172-173

Single-cell profiling of the immune landscape across the human lifespan.

DOI: https://doi.org/10.1038/s41590-024-02058-7
PLoS Pathog. 2025 Jan;21(1): e1012884

Guards and decoys: RIPoptosome and inflammasome pathway regulators of bacterial effector-triggered immunity.

Haleema Sadia Malik, James B Bliska.

Virulent microbes produce proteins that interact with host cell targets to promote pathogenesis. For example, virulent bacterial pathogens have proteins called effectors that are typically enzymes and are secreted into host cells. To detect and respond to the activities of effectors, diverse phyla of host organisms evolved effector-triggered immunity (ETI). In ETI, effectors are often sensed indirectly by detection of their virulence activities in host cells. ETI mechanisms can be complex and involve several classes of host proteins. Guards monitor the functional or physical integrity of another host protein, the guardee or decoy, and become activated to initiate an immune response when the guardee or decoy is modified or disrupted by an effector. A guardee typically has an intrinsic anti-pathogen function and is the intended target of an effector. A decoy structurally mimics a host protein that has intrinsic anti-pathogen activity and is unintentionally targeted by an effector. A decoy can be an individual protein, or a protein domain integrated into a guard. Here, we review the origins of ETI and focus on 5 mechanisms, in which the key steps of a pathway can include activation of a caspase by a RIPoptosome or inflammasome, formation of pores in the plasma membrane, release of cytokines and ending in cell death by pyroptosis. Survey of the 5 mechanisms, which have been shown to be host protective in mouse models of bacterial infection, reveal how distinct regulators of RIPoptosome or inflammasome pathways can act as guards or integrated decoys to trigger ETI. Common themes are highlighted and the limited mechanistic understanding of ETI bactericidal activity is discussed.

DOI: https://doi.org/10.1371/journal.ppat.1012884
Biomolecules. 2025 Jan 09. pii: 93. [Epub ahead of print]15(1):

From Cure to Crisis: Understanding the Evolution of Antibiotic-Resistant Bacteria in Human Microbiota.

Hamed Tahmasebi, Neda Arjmand, Marzieh Monemi, Ali Babaeizad, Farnaz Alibabaei, Negar Alibabaei, Aisa Bahar, Valentyn Oksenych, Majid Eslami.

  The growing prevalence of antibiotic-resistant bacteria within the human microbiome has become a pressing global health crisis. While antibiotics have revolutionized medicine by significantly reducing mortality and enabling advanced medical interventions, their misuse and overuse have led to the emergence of resistant bacterial strains. Key resistance mechanisms include genetic mutations, horizontal gene transfer, and biofilm formation, with the human microbiota acting as a reservoir for antibiotic resistance genes (ARGs). Industrialization and environmental factors have exacerbated this issue, contributing to a rise in infections with multidrug-resistant (MDR) bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant Enterobacteriaceae. These resistant pathogens compromise the effectiveness of essential treatments like surgical prophylaxis and chemotherapy, increase healthcare costs, and prolong hospital stays. This crisis highlights the need for a global One-Health approach, particularly in regions with weak regulatory frameworks. Innovative strategies, including next-generation sequencing (NGS) technologies, offer promising avenues for mitigating resistance. Addressing this challenge requires coordinated efforts, encompassing research, policymaking, public education, and antibiotic stewardship, to safeguard current antibiotics and foster the development of new therapeutic solutions. An integrated, multidimensional strategy is essential to tackle this escalating problem and ensure the sustainability of effective antimicrobial treatments.

Keywords:  antibiotic-resistant; crisis; evolution; hospital-acquired infections; microbiota

DOI:  https://doi.org/10.3390/biom15010093
Redox Rep. 2025 Dec;30(1): 2444755

CEACAM5 exacerbates asthma by inducing ferroptosis and autophagy in airway epithelial cells through the JAK/STAT6-dependent pathway.

Si Liu, Li Chen, Yunxiao Shang.

   OBJECTIVES: Asthma, a prevalent chronic disease, poses significant health threats and burdens healthcare systems. This study focused on the role of bronchial epithelial cells in asthma pathophysiology.
METHODS: Bioinformatics was used to identify key asthmarelated genes. An ovalbumin-sensitized mouse model and an IL-13-stimulated Beas-2B cell model were established for further investigation.
RESULTS: Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) was identified as a crucial gene in asthma. CEACAM5 expression was elevated in asthmatic mouse lung tissues and IL-13-stimulated Beas-2B cells, primarily in bronchial epithelial cells. CEACAM5 induced reactive oxygen species (ROS), lipid peroxidation, and ferroptosis. Interfering with CEACAM5 reduced ROS, malondialdehyde levels, and enhanced antioxidant capacity, while inhibiting iron accumulation and autophagy. Overexpression of CEACAM5 in IL-13-stimulated cells activated the JAK/STAT6 pathway, which was necessary for CEACAM5-induced autophagy, ROS accumulation, lipid peroxidation, and ferroptosis.
CONCLUSION: CEACAM5 promotes ferroptosis and autophagy in airway epithelial cells via the JAK/STAT6 pathway, exacerbating asthma symptoms. It represents a potential target for clinical treatment.

Keywords:  Bronchial epithelial cells; CEACAM5; JAK; STAT6; autophagy; ferroptosis

DOI:  https://doi.org/10.1080/13510002.2024.2444755
J Tissue Eng. 2025 Jan-Dec;16:16 20417314241299076

Developing human upper, lower, and deep lung airway models: Combining different scaffolds and developing complex co-cultures.

Rasika S Murkar, Cornelia Wiese-Rischke, Tobias Weigel, Sascha Kopp, Heike Walles.

  Advanced in vitro models are crucial for studying human airway biology. Our objective was the development and optimization of 3D in vitro models representing diverse airway regions, including deep lung alveolar region. This initiative was aimed at assessing the influence of selective scaffold materials on distinct airway co-culture models. While PET membranes (30 µm thickness) were unsuitable for alveolar models due to their stiffness and relatively high Young's modulus, a combination of collagenous scaffolds seeded with Calu-3 cells and fibroblasts, showed increased mucus production going from week 1 to week 4 of air lift culture. Meanwhile standard electrospun polymer membrane (50-60 µm thick), which possesses a considerably low modulus of elasticity, offered higher flexibility and supported co-cultures of primary alveolar epithelial (huAEC) and endothelial cells (hEC) in concert with lung biopsy-derived fibroblasts which enhanced maturation of the tissue model. As published, designing human alveolar in vitro models require thin scaffold to mimic the required ultra-thin ECM, in addition to assuring right balanced AT1/AT2 ratio for biomimetic representation. We concluded that co-cultivation of primary/stem cells or cell lines has a higher influence on the function of the airway tissue models than the applied scaffolds.

Keywords:  3D microenvironment; Airway tissue models; cell lines (Calu-3 and A549); co-culture; collagenous and synthetic scaffold biomaterial; deep lung alveoli; electrospinning; extracellular matrix (ECM); lower airway; primary human cells and stem cells; upper airway

DOI:  https://doi.org/10.1177/20417314241299076
Microorganisms. 2025 Jan 08. pii: 110. [Epub ahead of print]13(1):

Mycobacteria Exploit Host GPR84 to Dampen Pro-Inflammatory Responses and Promote Infection in Macrophages.

Reziya Wumaier, Ke Zhang, Jing Zhou, Zilu Wen, Zihan Chen, Geyang Luo, Hao Wang, Juliang Qin, Bing Du, Hua Ren, Yanzheng Song, Qian Gao, Bo Yan.

  Tuberculosis (TB) remains the major cause of mortality and morbidity, causing approximately 1.3 million deaths annually. As a highly successful pathogen, Mycobacterium tuberculosis (Mtb) has evolved numerous strategies to evade host immune responses, making it essential to understand the interactions between Mtb and host cells. G-protein-coupled receptor 84 (GPR84), a member of the G-protein-coupled receptor family, contributes to the regulation of pro-inflammatory reactions and the migration of innate immune cells, such as macrophages. Its role in mycobacterial infection, however, has not yet been explored. We found that GPR84 is induced in whole blood samples from tuberculosis patients and Mycobacterium marinum (Mm)-infected macrophage models. Using a Mm-wasabi infection model in mouse tails, we found that GPR84 is an important determinant of the extent of tissue damage. Furthermore, from our studies in an in vitro macrophage Mm infection model, it appears that GPR84 inhibits pro-inflammatory cytokines expression and increases intracellular lipid droplet (LD) accumulation, thereby promoting intracellular bacterial survival. Our findings suggest that GPR84 could be a potential therapeutic target for host-directed anti-TB therapeutics.

Keywords:  G-protein-coupled receptors 84 (GPR84); pro-inflammatory cytokines; tuberculosis (TB)

DOI:  https://doi.org/10.3390/microorganisms13010110
Respir Res. 2025 Jan 30. 26(1): 45

NTHi killing activity is reduced in COPD patients and is associated with a differential microbiome.

MICA II Study Group

  Chronic obstructive pulmonary disease (COPD) is a chronic lung disease characterized by airway obstruction and inflammation. Non-typeable Haemophilus influenzae (NTHi) lung infections are common in COPD, promoting frequent exacerbations and accelerated lung function decline. The relationship with immune responses and NTHi are poorly understood. Herein, we comprehensively characterized the respiratory microbiome and mycobiome of patients while investigating microbial dynamics and host immune changes attributable to NTHi killing activity. Mild-to-moderate COPD patients encompassing frequent and infrequent exacerbators and healthy volunteers (HV) were enrolled. Microbial composition, proteomics and NTHi killing activity was analyzed using bronchoalveolar lavage fluid (BALF). In addition, antigen-antibody titers in sera to COPD pathogens were determined using a multiplex assay. Differential abundance analysis revealed an enrichment of Actinobacteria and Bacteroidetes in the BALF of COPD and HV subjects respectively. Significant differences in the IgA titer response were observed against NTHi antigens in COPD vs. HV. Notably, there was also significantly greater killing activity against NTHi in BALF from COPD vs. HV subjects (OR = 5.64; 95% CI = 1.75-20.20; p = 0.001). Stratification of COPD patients by NTHi killing activity identified unique microbial and protein signatures wherein Firmicutes, Actinobacteria and haptoglobin were enriched in patients with killing activity. We report that differences in host immune responses and NTHi-killing activity are associated with microbiome changes in mild-to-moderate COPD. This is suggestive of a potential link between the respiratory microbiome and immune activity against NTHi in the context of COPD pathogenesis even at this disease stage.

Keywords:  COPD; Exacerbations; Microbiome; Non-typeable Haemophilus influenzae

DOI:  https://doi.org/10.1186/s12931-025-03113-z
J Crohns Colitis. 2025 Jan 28. pii: jjaf016. [Epub ahead of print]

Intestinal Epithelial Ptpn23 Is Essential For Gut Barrier Integrity And Prevention Of Fatal Bacterial Translocation.

Rocio Sanchez Alvarez, Ana Montalban-Arques, Yasser Morsy, Claudia Gottier, Janine Häfliger, Kirstin Atrott, Anna Bircher, Egle Katkeviciute, Doris Pöhlmann, Luise Linzmeier, Madita Determann, Céline Mamie, Anna Niechcial, Marlene Schwarzfischer, Sebastian Zeissig, Silvia Lang, Michael Scharl, Marianne Spalinger.

   BACKGROUND AND AIMS: Protein tyrosine phosphatase non-receptor type 23 (PTPN23) regulates the internalization of growth factor receptors such as the epithelial growth factor receptor (EGFR). Given the crucial function of such receptors in intestinal epithelial cells (IECs), we assessed the involvement of PTPN23 in intestinal homeostasis and epithelial proliferation.
METHODS: We generated mouse models with constitutive (PTPN23fl/flVilCre+/-) or inducible (PTPN23fl/flVilCreERT+/-) deletion of PTPN23 in IEC. To elucidate the functional consequences of PTPN23 deletion in IEC, we performed barrier function studies, flow cytometry, RNAseq and in vivo experiments applying EGFR inhibition, antibiotic treatment, or co-housing approaches to further delineate the observed phenotype.
RESULTS: Deletion of PTPN23 in IECs resulted in a severe early-onset phenotype in both models. Mice were characterized by elongated colon, epithelial hyperproliferation, splenomegaly and diarrhea leading to the death of the mice within 3 weeks of PTNP23 deletion. Compromised gut barrier integrity resulted in enhanced bacterial translocation accompanied by reduced IgA transcytosis in PTPN23fl/flVilCreERT+/- compared to wild-type mice. Although EGFR surface expression was increased upon PTPN23-deletion, inhibition of EGFR signaling did not prevent disease. In contrast, and in accordance with defective bacterial handling, antibiotic treatment, but not co-housing, fully rescued the phenotype.
CONCLUSION: The absence of PTPN23 in IECs leads to lethal dysregulation of intestinal homeostasis, triggered by bacterial infiltration due to defects in the intestinal epithelial barrier and impaired IgA transcytosis. Thus, we identify PTPN23 as a novel key player in preserving intestinal epithelial homeostasis, ultimately preventing bacterial overgrowth and excessive immune activation in the intestine.

Keywords:  Intestinal homeostasis; intestinal epithelial cells; transcytosis

DOI:  https://doi.org/10.1093/ecco-jcc/jjaf016
Pulmonology. 2025 Dec 31. 31(1): 2411807

Countering antimicrobial resistance.

B Adhikari, P Parajuli, S Lippmann.



Keywords:  Antimicrobial resistance; antimicrobial stewardship; one health; swann report

DOI:  https://doi.org/10.1080/25310429.2024.2411807
Adv Sci (Weinh). 2025 Jan 30. e2406218

Single-Cell Landscape of Bronchoalveolar Lavage Fluid Identifies Specific Neutrophils during Septic Immunosuppression.

Rong Shen, Yi Jiang, Guanglong Liu, Shenjia Gao, Hao Sun, Xinyi Wu, Jiahui Gu, Han Wu, Ke Mo, Xing Niu, Ronen Ben-Ami, Wanjing Shang, Jie Zhang, Jun Wang, Changhong Miao, Zhizhang Wang, Wankun Chen.

  Sepsis-induced immunosuppression is related to increased susceptibility to secondary infections and death. Lung is the most vulnerable target organ in sepsis, but the understanding of the pulmonary immunosuppression state is still limited. Here, single-cell RNA sequencing of bronchoalveolar lavage fluid (BALF) is performed to map the landscape of immune cells, revealing a neutrophil-driven immunosuppressive program in the lungs of patients with immunosuppressive sepsis. Although immunosuppressive genes are upregulated in different immune cells, only neutrophils dramatically increase in the BALF of patients in immunosuppressive phase of sepsis. Five neutrophil subpopulations in BALF are identified, among which CXCR2+ and CD274 (PD-L1 coding gene)+IL1RN+ neutrophil subpopulations increased significantly during septic immunosuppression. Interestingly, a developmental trajectory from CXCR2+ to CD274+IL1RN+ neutrophil subpopulation is disclosed. Moreover, the therapeutic effect of CXCR2 blockade is observed on the survival of septic mice, along with a decreased number of PD-L1+ neutrophils. Taken together, the CXCR2+ neutrophil subpopulation is discovered as a contributor to immunosuppression in sepsis and identified it as a potential therapeutic target in sepsis treatment.

Keywords:  CXCR2; bronchoalveolar lavage fluid; neutrophils; sepsis; single‐cell RNA sequencing

DOI:  https://doi.org/10.1002/advs.202406218
bioRxiv. 2025 Jan 14. pii: 2025.01.10.632380. [Epub ahead of print]

Physiologically Relevant Coculture Model for Oral Microbial-Host Interactions.

Zeyang Pang, Nicole Cady, Lujia Cen, Thomas M Schmidt, Xuesong He, Jiahe Li.

Understanding microbial-host interactions in the oral cavity is essential for elucidating oral disease pathogenesis and its systemic implications. In vitro bacteria-host cell coculture models have enabled fundamental studies to characterize bacterial infection and host responses in a reductionist yet reproducible manner. However, existing in vitro coculture models fail to replicate the physiological oxygen gradients critical for studying these interactions. Here, we present an asymmetric gas coculture system that simulates the oral microenvironment by maintaining distinct normoxic and anaerobic conditions for gingival epithelial cells and anaerobic bacteria, respectively. Using Fusobacterium nucleatum , a key oral pathobiont, we demonstrate that the system preserves bacterial viability and supports the integrity of telomerase-immortalized gingival keratinocytes. Compared to conventional models, this system enhanced bacterial invasion, elevated intracellular bacterial loads, and elicited more robust host pro-inflammatory responses, including increased secretion of CXCL10, IL-6, and IL-8. Additionally, the model enabled precise evaluation of antibiotic efficacy against intracellular pathogens. These results underscore the utility of this coculture platform for studying oral microbial pathogenesis and screening therapeutics, offering a physiologically relevant approach to advance oral and systemic health research.
TOC:

DOI: https://doi.org/10.1101/2025.01.10.632380
FASEB J. 2025 Jan 15. 39(1): e70301

Sepsis-induced NET formation requires MYD88 but is independent of GSDMD and PAD4.

Hanna Englert, Chandini Rangaswamy, Giuliano A Kullik, Mylène Divivier, Josephine Göbel, Irm Hermans-Borgmeyer, Uwe Borgmeyer, Kerri A Mowen, Manu Beerens, Maike Frye, Reiner K Mailer, Mathias Gelderblom, Evi X Stavrou, Roger J S Preston, Stefan W Schneider, Tobias A Fuchs, Thomas Renné.

  Neutrophils are peripheral blood-circulating leukocytes that play a pivotal role in host defense against bacterial pathogens which upon activation, they release web-like chromatin structures called neutrophil extracellular traps (NETs). Here, we analyzed and compared the importance of myeloid differentiation factor 88 (MYD88), peptidyl arginine deiminase 4 (PAD4), and gasdermin D (GSDMD) for NET formation in vivo following sepsis and neutrophilia challenge. Injection of lipopolysaccharide (LPS)/E. coli or the transgenic expression of granulocyte colony-stimulating factor (G-CSF), each induced NET-mediated lethal vascular occlusions in mice with combined genetic deficiency in Dnase1 and Dnase1l3 (D1/D1l3-/-). In accordance with the signaling of toll-like receptors, Myd88/D1/D1l3-/- animals were protected from the formation of lethal intravascular NETs during septic conditions. However, this protection was not observed during neutrophilia. It was unexpected to find that both Gsdmd/D1/D1l3-/- and Pad4/D1/D1l3-/- mice were fully capable of forming NETs upon LPS/E.coli challenge. Sepsis equally triggered a similar inflammatory response in these mice characterized by formation of DNA-rich thrombi, vessel occlusions, and mortality from pulmonary embolism, compared to D1/D1l3-/- mice. Pharmacologic GSDMD inhibitors did not reduce PMA-stimulated NET formation in ex vivo models either. Similarly, neither Pad4 nor GSDMD deficiency affected intravascular occlusive NET formation upon neutrophilia challenge. The magnitude of NET production, multi-organ damage, and lethality were comparable to those observed in challenged control mice. In conclusion, our data indicate that NET formation during experimental sepsis and neutrophilia is regulated by distinct stimulus-dependent pathways that may be independent of canonical PAD4 and GSDMD.

Keywords:  GSDMD; PAD4; immunothrombosis; inflammation; neutrophil extracellular traps; vascular biology

DOI:  https://doi.org/10.1096/fj.202402514R
Infect Control Hosp Epidemiol. 2025 Jan 27. 1-4

Heterogeneity in preoperative Staphylococcus aureus screening and decolonization strategies among healthcare institutions.

Sarah L Bennis, Shalini Kulasingam, Patricia Ferrieri, Susan E Kline.

We surveyed 111 institutions' practices for screening and decolonization of Staphylococcus aureus in presurgical patients. Institutions commonly utilize universal, targeted, or no decolonization strategies. Frequently reported products were nasal mupirocin, chlorhexidine gluconate bathing, and nasal povidone-iodine. Practice variability indicates opportunities to define optimal strategies.

DOI: https://doi.org/10.1017/ice.2024.231
Int Immunopharmacol. 2025 Jan 23. pii: S1567-5769(25)00108-0. [Epub ahead of print]148 114119

Histone lactylation regulates PRKN-Mediated mitophagy to promote M2 Macrophage polarization in bladder cancer.

Xiaolin Deng, Yuan Huang, Jinge Zhang, Yuwen Chen, Feifan Jiang, Zicai Zhang, Tanghua Li, Lina Hou, Wanlong Tan, Fei Li.

   BACKGROUND: Bladder cancer (BCa), particularly muscle-invasive bladder cancer (MIBC), is associated with poor prognosis, partly because of immune evasion driven by M2 tumor-associated macrophages (TAMs). Understanding the regulatory mechanisms of M2 macrophage polarization via PRKN-mediated mitophagy and histone lactylation (H3K18la) is crucial for improving treatment strategies.
METHODS: A single-cell atlas from 46 human BCa samples was constructed to identify macrophage subpopulations. Bioinformatics analysis and experimental validation, including ChIP-seq and lactylation modulation assays, were used to investigate the role of PRKN in M2 macrophage polarization and its regulation by H3K18la.
RESULTS: Single-cell analysis revealed distinct macrophage subpopulations, including M1 and M2 types. PRKN was identified as a critical regulator of mitophagy in M2 macrophages, supporting their immunosuppressive function. Bulk RNA-seq and gene intersection analysis revealed a set of mitophagy-related macrophage polarization genes (Mito_Macro_RGs) enriched in mitophagy and immune pathways. Pseudotime analysis revealed that PRKN was upregulated during the M1-to-M2 transition. siRNA-mediated PRKN knockdown impaired M2 polarization, reducing the expression of CD206 and ARG1. ChIP-seq and histone lactylation modulation confirmed that H3K18la enhanced PRKN expression, promoting mitophagy and M2 polarization and thereby facilitating immune suppression and tumor progression.
CONCLUSIONS: Histone lactylation regulated PRKN-mediated mitophagy, promoting M2 macrophage polarization and contributing to immune evasion in BCa.

Keywords:  Bladder cancer; H3K18la; M2 macrophage polarization; Mitophagy; PRKN

DOI:  https://doi.org/10.1016/j.intimp.2025.114119
Adv Biotechnol (Singap). 2024 Sep 03. 2(3): 29

DSCI: a database of synthetic biology components for innate immunity and cell engineering decision-making processes.

Chenqiu Zhang, Tianjian Chen, Zhiyu Li, Qing Lu, Xiaotong Luo, Sihui Cai, Jie Zhou, Jian Ren, Jun Cui.

  Although significant progress of clinical strategy has been made in gene editing and cell engineering in immunotherapy, it is now apparent that design and modification in terms of complex signaling pathways and motifs on medical synthetic biology are still full of challenges. Innate immunity, the first line of host defense against pathogens, is critical for anti-pathogens immune response as well as regulating durable and protective T cell-mediated anti-tumor responses. Here, we introduce DSCI (Database of Synthetic Biology Components for Innate Immunity, https://dsci.renlab.cn/ ), a web-accessible and integrative database that provides better insights and strategies for innate immune signaling circuit design in biosynthesis. Users can interactively navigate comprehensive and carefully curated components resources that presented as visualized signaling motifs that participate in innate immunity. The current release of DSCI incorporates 1240 independent components and more than 4000 specific entries contextually annotated from public literature with experimental verification. The data integrated into DSCI includes the components of pathways, relationships between regulators, signal motifs based on regulatory cascades, and loop graphs, all of which have been comprehensively annotated to help guide modifications to gene circuits. With the support of DSCI, users can easily obtain guidance of gene circuits construction to make decision of cell engineering based on innate immunity. DSCI not only provides comprehensive and specialized resource on the biological components of innate immune synthesis, but also serves as a useful tool to offer modification or generation strategies for medical synthetic biology.

Keywords:  Database; Innate immunity; Interaction network; Loop visualization; Signal motif; Synthetic biology

DOI:  https://doi.org/10.1007/s44307-024-00036-6
J Clin Invest. 2025 Jan 30. pii: e176865. [Epub ahead of print]

Monocytes and interstitial macrophages contribute to hypoxic pulmonary hypertension.

Rahul Kumar, Kevin Nolan, Biruk Kassa, Neha Chanana, Tsering Palmo, Kavita Sharma, Kanika Singh, Claudia Mickael, Dara Fonseca Balladares, Julia Nilsson, Amit Prabhakar, Aastha Mishra, Michael H Lee, Linda Sanders, Sushil Kumar, Ari B Molofsky, Kurt R Stenmark, Dean Sheppard, Rubin M Tuder, Mohit D Gupta, Tashi Thinlas, Qadar Pasha, Brian B Graham.

  Hypoxia is a major cause of pulmonary hypertension (PH) worldwide, and it is likely that interstitial pulmonary macrophages contribute to this vascular pathology. We observed in hypoxia-exposed mice an increase in resident interstitial macrophages, which expanded through proliferation and expressed the monocyte recruitment ligand CCL2. We also observed an increase in CCR2+ macrophages through recruitment, which express the protein thrombospondin-1 that functionally activates TGF-beta to cause vascular disease. Blockade of monocyte recruitment with either CCL2 neutralizing antibody treatment or CCR2 deficiency in the bone marrow compartment suppressed hypoxic PH. These data were supported by analysis of plasma samples from humans who travelled from low (225m) to high (3500m) elevation, revealing an increase in thrombospondin-1 and TGF-beta expression following ascent, which was blocked by dexamethasone prophylaxis. In the hypoxic mouse model, dexamethasone prophylaxis recapitulated these findings by mechanistically suppressing CCL2 expression and CCR2+ monocyte recruitment. These data suggest a pathologic cross-talk between two discrete interstitial macrophage populations, which can be therapeutically targeted.

Keywords:  Chemokines; Hypoxia; Inflammation; Monocytes; Vascular biology

DOI:  https://doi.org/10.1172/JCI176865
Infect Immun. 2025 Jan 29. e0040724

Evidence that staphylococcal superantigens promote within-patient bacterial persistence following post-operative surgical site infection.

Karine Dufresne, Stephen W Tuffs, Nicholas R Walton, Katherine J Kasper, Ivor Mohorovic, Farah Hasan, Tracey Bentall, David E Heinrichs, Johan Delport, Tina S Mele, John K McCormick.

  Staphylococcus aureus is a predominant cause of post-operative surgical site infections and persistent bacteremia. Here, we describe a patient who experienced three episodes of S. aureus infection over a period of 4 months following a total knee arthroplasty. The initial bloodstream isolate (SAB-0429) was a clonal complex 5 (CC5) and methicillin-resistant S. aureus (MRSA), whereas two subsequent isolates (SAB-0485 and SAB-0495) were CC5 isolates but methicillin-sensitive S. aureus. The two latter isolates harbored a plasmid encoding three superantigen genes that were not present in the primary MRSA isolate. SAB-0485 and SAB-0495 both expressed the plasmid-encoded staphylococcal enterotoxin R exotoxin and demonstrated increased superantigen activity compared with SAB-0429. Compared to SAB-0429, the latter isolates also demonstrated an increased bacterial burden in a mouse bacteremia model that was dependent on increased interferon-γ production. Curing of the plasmid from SAB-0485 reduced this virulence phenotype. These findings suggest that the superantigen exotoxins may provide a selective advantage in chronic post-surgical infections.IMPORTANCEIn this study, we investigated bacterial isolates from a patient who experienced three recurrent S. aureus infections over a 4 month period following total knee arthroplasty. Genomic and phenotypic characterization of these isolates revealed that they all belonged to clonal complex 5, yet the latter two strains contained an additional plasmid encoding superantigen exotoxins. Subsequent experimental infection experiments in mice demonstrated that the plasmid-encoded superantigens exacerbated bacteremia by promoting liver abscess formation. These experiments suggest that despite appropriate antibiotic therapy, bacterial superantigens may be able to promote persistent infection following post-surgery.

Keywords:  Staphylococcus aureus; bacteremia; superantigen; surgical site infection

DOI:  https://doi.org/10.1128/iai.00407-24
Am J Transplant. 2025 Jan 28. pii: S1600-6135(25)00043-7. [Epub ahead of print]

HMGB1-mediated CIITA super-enhancers are critical for DC trained immunity in acute-to-chronic progression of allograft rejection.

Lingjuan Sun, Xiangli Zhao, Xiaosheng Tan, Liu Song, Zhibo Ma, Jingzeng Wang, Peixiang Lan, Song Chen, Gang Chen.

  Chronic allograft rejection is mainly mediated by indirect recognition. Dendritic cells (DCs), as the major antigen-presenting cells in indirect recognition, exhibit an enhanced antigen-presenting ability in chronic rejection, but the specific mechanism is still unclear. Here, we found that pretreatment with high mobility group box-1 protein (HMGB1) in vivo can induce trained immunity in DCs. These trained DCs demonstrated an enhanced ability to present alloantigen, accelerating allograft rejection in a CTLA4-Ig-induced chronic rejection model by upregulating the expression of MHC-II and class II major histocompatibility complex transactivator (CIITA) molecules. Mechanistically, we found that HMGB1 promoted the formation of super-enhancers (SEs) of CIITA, epigenetically reprogramming DCs and promoting trained immunity. The SEs inhibitor JQ1 reduced the expression of CIITA and MHC-II in DCs, thereby delaying the occurrence of chronic rejection. Interestingly, we identified HMGB1 as a specific inducer of SE formation in a newly named SEa region of CIITA. Targeted knockout of the CIITA's SEa region inhibited HMGB1-induced trained immunity in DCs. Taken together, our data confirm that HMGB1 can induce the formation of the SEs of CIITA, promote trained immunity in DCs, and accelerate allograft rejection, thus offering a new potential target for the treatment of chronic rejection.

Keywords:  CIITA; DC; HMGB1; chronic rejection; super enhancer; trained immunity

DOI:  https://doi.org/10.1016/j.ajt.2025.01.037
J Genet Genomics. 2025 Jan 23. pii: S1673-8527(25)00024-4. [Epub ahead of print]

Multifaceted interplays between the essential players and lipid peroxidation in ferroptosis.

Conghe Liu, Zhihao Liu, Zheng Dong, Sijin Liu, Haidong Kan, Shuping Zhang.

  Ferroptosis, a type of programmed cell death, represents a distinct paradigm in cell biology. It is characterized by the iron-dependent accumulation of reactive oxygen species, which induce lipid peroxidation (LPO), and is orchestrated by the interplay between iron, lipid peroxides, and glutathione. In this review, we emphasize the frequently overlooked role of iron in LPO beyond the classical iron-driven Fenton reaction in several crucial processes that regulate cellular iron homeostasis, including iron intake and export as well as ferritinophagy, and the emerging roles of endoplasmic reticulum-resident flavoprotein oxidoreductases, especially P450 oxidoreductases, in modulating LPO. We summarize how various types of fatty acids (FAs), including saturated, monounsaturated, and polyunsaturated FAs, differentially influence ferroptosis when incorporated into phospholipids. Furthermore, we highlight the therapeutic potential of targeting LPO to mitigate ferroptosis and discuss the regulatory mechanisms of endogenous lipophilic radical-trapping antioxidants that confer resistance to ferroptosis, shedding light on therapeutic avenues for ferroptosis-associated diseases.

Keywords:  Fatty acids; Ferroptosis; Flavoprotein oxidoreductases; Lipid peroxidation; Radical-trapping antioxidants

DOI:  https://doi.org/10.1016/j.jgg.2025.01.009