bims-traimu 2026-10-18 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–10–18
nineteen papers selected by
Yantong Wan, Southern Medical University

The epigenetic-metabolic axis of trained immunity: dual roles in disease pathogenesis and intervention.
Epigenetic and Metabolic Changes That Drive Trained Immunity in Response to Microbes and Vaccines.
Trained immunity in chronic, relapsing and low-grade joint inflammation.
Trained immunity in cancer immunotherapy and vaccine development: mechanisms, evidence gaps, and translational opportunities.
Transient manganese exposure reprograms bone marrow-derived macrophages toward a stable anti-inflammatory memory state.
From marrow memory to adverse ventricular remodeling: trained immunity after myocardial infarction.
Programming innate immune memory: The context-dependent role of type I interferons.
Damage-Associated Molecular Patterns and Trained Immunity of Monocyte-Macrophage Populations in Osteoarthritis: Potential Molecular Links and Therapeutic Opportunities.
Inflammatory memory as a potential driver of rosacea pathogenesis: integrating mechanisms of chronic relapse and perspectives on disease modification.
Allergen-induced trained immunity in alveolar macrophages predisposes to long-lasting airway hypersensitivity.
Perinatal nicotine exposure disrupts hematopoietic stem cell development and elevates influenza severity in adulthood.
Isorhapontigenin alleviates sepsis-induced acute lung injury by targeting the RAF1-ERK1/2-CXCL10 axis to inhibit CXCR3+ neutrophil recruitment.
Author Correction: Monocyte-derived galectin-1hi cells provide innate immune help in the generation of functional memory CD8+ T cells.
A helminth-microbiota metabolic relay promotes disease tolerance.
Macrophages as programmable integrators of disease tolerance across lifespan.
Opsonic Peptide MOP3 Attenuates Ischemic Acute Kidney Injury.
Early post-sepsis innate behavioral changes in aged mice occur independently of detectable neuroinflammation.
USP25 augments XIAP-mediated signaling to safeguard intestinal homeostasis.
Embracing macrophage complexity for research and translation.

J Mol Med (Berl). 2026 Oct 14. pii: 121. [Epub ahead of print]104(1):

The epigenetic-metabolic axis of trained immunity: dual roles in disease pathogenesis and intervention.

Liqi Liao, Zhe Zhai, Linglin Zhong, Chenyu Shi, Shunyu Yao, Lingling Tao, Yong-Xian Cheng, Xuhan Liu.

  As early as 1931, bacillus Calmette-Guérin (BCG) vaccination was hypothesized to reduce neonatal mortality through nonspecific immune stimulation. The concept of trained immunity was formally proposed in the 21st century, and clinical observations during the COVID-19 pandemic further stimulated interest in the possibility that BCG vaccination might confer broad, non-specific protection against heterologous infections. Trained immunity represents a paradigm-shifting concept in immunology, defining the innate immune system's ability to develop a memory-like state through persistent epigenetic and metabolic reprogramming following initial stimulus exposure. This process enables enhanced, nonspecific responses upon re-exposure, extending immune memory beyond adaptive immunity. The dual role of trained immunity is context-dependent: it is protective in acute infections by improving pathogen clearance, but pathogenic in chronic conditions such as atherosclerosis and certain tumor microenvironments, where sustained proinflammatory memory promotes disease progression. Central mechanisms involve mTOR-HIF-1α signaling, metabolic rewiring of mevalonate/cholesterol pathways, and histone modifications including H3K4me3 and H3K27ac. This review systematically synthesizes the cellular basis, inducing factors, and disease spectrum of trained immunity, providing a conceptual framework for advancing host-directed therapies and precision immunology in infectious, inflammatory, and oncological contexts.

Keywords:  Chronic inflammation; Epigenetic reprogramming; Infectious diseases; Metabolic rewiring; Oncology; Trained immunity

DOI:  https://doi.org/10.1007/s00109-026-02729-y
Immunology. 2026 Oct 16.

Epigenetic and Metabolic Changes That Drive Trained Immunity in Response to Microbes and Vaccines.

Desalegn Abebaw, Aytenew Atnaf, Bantayehu Addis Tegegne, Abebe Fenta, Bantegzie Selabat, Temesgen Baylie, Yonatan Kindie, Zigale Hibstu Teffera, Mekuriaw Belayneh, Mohammed Jemal, Adane Adugna.

  Trained immunity is a form of innate immune memory in which initial exposure to microbial components or vaccines leads to long-lasting functional reprogramming of innate immune cells through epigenetic and metabolic changes. Unlike adaptive immunity, it does not rely on B or T lymphocytes and provides broad, nonspecific protection against various pathogens. This phenomenon has been observed across a range of immune cells, including monocytes, macrophages, neutrophils, NK cells and even γδ T-cells, as well as at the level of haematopoietic stem and progenitor cells (HSPCs). Key inducers include microbial products (e.g., β-glucan, BCG and MMR vaccines), metabolic byproducts (e.g., mevalonate and lactate) and cytokines such as IL-1β. These agents activate signalling pathways such as the Akt/mTOR/HIF-1α pathway and lead to chromatin remodelling via histone modifications such as H3K4me3 and H3K9me3. Immunometabolism plays a pivotal role, with trained cells shifting toward glycolysis, glutaminolysis and cholesterol synthesis. Lactate and fumarate further link metabolism to epigenetic remodelling. Notably, trained immunity can be protective in infectious diseases and beneficial in noninfectious contexts, such as cancer immunotherapy and autoimmune regulation. This review provides a comprehensive overview of the cellular, epigenetic and metabolic mechanisms underlying trained immunity, highlighting how innate immune cells acquire memory-like properties independent of adaptive immunity. This study also provides insights into the therapeutic potential of leveraging trained immunity for vaccine development, infection control and immunomodulation in noninfectious diseases.

Keywords:  epigenetic alteration; immunometabolism; microbial components; trained immunity; vaccine

DOI:  https://doi.org/10.1111/imm.70216
Nat Rev Rheumatol. 2026 Oct 12.

Trained immunity in chronic, relapsing and low-grade joint inflammation.

Brenda Kischkel, Sonia Nasi, Charles Leroy, Leo A B Joosten, Hang Korng Ea.

Trained immunity is a form of innate immune memory mediated by metabolic and epigenetic reprogramming that promotes sustained inflammatory responses. Accumulating evidence implicates a role for maladaptive trained immunity in sustaining inflammation and promoting disease progression across distinct forms of inflammatory joint disease, including rheumatoid arthritis, gout, calcium pyrophosphate deposition disease and osteoarthritis. Inflammatory cytokines, damage-associated patterns and metabolic signals can induce long-lasting inflammatory programmes in both immune cells, such as monocytes and macrophages, and non-immune cells within the joint, such as chondrocytes and synovial-like fibroblasts. Trained immunity also provides a potential mechanistic link between joint inflammation and associated systemic complications, including increased cardiovascular risk. Therapeutic strategies targeting the metabolic and epigenetic pathways that underlie trained immunity could offer opportunities to limit chronic inflammation, prevent structural damage and reduce disease-associated comorbidities.

DOI: https://doi.org/10.1038/s41584-026-01439-6
Front Immunol. 2026 ;17 1939256

Trained immunity in cancer immunotherapy and vaccine development: mechanisms, evidence gaps, and translational opportunities.

Lian Yang, Jianfeng Liu, Shufei Zhang, Yong He, Jiaxu Chen, Donghui Tan.

  Breakthroughs in cancer immunotherapy have been overwhelmingly driven by advances in adaptive immunity, leaving the therapeutic potential of innate immunity largely untapped, a gap in the current treatment paradigm. Trained immunity, defined by the durable, mitotically maintained metabolic and epigenetic memory that innate immune cells acquire after transient stimulation, offers a new approach to addressing this deficit. Here we survey the triggering signals, cellular heterogeneity, and molecular circuitry that govern trained immunity within the tumor microenvironment. We dissect its dualistic character: the mechanistic basis by which trained immunity can either restrain or promote tumor progression, and what this ambivalence means for the design of next-generation immunotherapies. These insights inform a growing pipeline of trained-immunity-based cancer vaccines, which we categorize into four engineered platforms, recombinant BCG, β-glucan nanoformulations, lipid nanoparticle (LNP)-mRNA bifunctional vaccines, and commensal-derived adjuvants. We further propose that vaccine efficacy may depend in part on host immune context, and outline stratification strategies and dosing schedules that may need to be adjusted according to individual immune status, pending clinical validation. In aggregate, evidence from human bladder cancer, preclinical tumor models, and non-tumor trained immunity studies suggests that trained immunity could elevate innate immunity from a supporting role toward an independent therapeutic axis, although most of its direct cancer applications remain at the preclinical or conceptual stage.

Keywords:  cancer immunotherapy; cancer vaccine; innate immunity; metabolic reprogramming; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2026.1939256
J Immunol. 2026 Oct 01. pii: vkag267. [Epub ahead of print]215(10):

Transient manganese exposure reprograms bone marrow-derived macrophages toward a stable anti-inflammatory memory state.

Yang Luo, Yu Cheng, Jia Zhang, Linying Li, Shih-Chin Cheng.

  Manganese ions (Mn2+) are potent immunomodulatory agents that activate the cGAS-STING pathway. While their role as acute adjuvants is well-documented, the innate immune memory (trained immunity) signatures induced by Mn2+ remain unexplored. Using an in vitro priming-rest-challenge model, we demonstrate that transient Mn2+ stimulation induces a persistent anti-inflammatory state in bone marrow-derived macrophages (BMDMs). Unlike the immediate proinflammatory burst associated with Mn2+, Mn2+-trained BMDMs displayed a stable reduction in Il6, Il1b, Il12a, and Nos2 expression upon secondary LPS or LPS + IFN-γ challenge. Furthermore, Mn2+ training enhanced IL-4-driven Arg1 induction and suppressed MHC class II surface expression, antigen presentation pathways, and phagocytic capacity against Candida albicans. Mechanistically, this functional attenuation was independent of glycolysis but correlated with a broad downregulation of lipid metabolic pathways. These findings reveal a lineage-specific regulatory "brake" induced by manganese, providing critical insights for its application in immunotherapy.

Keywords:  macrophage; manganese; trained immunity

DOI:  https://doi.org/10.1093/jimmun/vkag267
Front Immunol. 2026 ;17 1962412

From marrow memory to adverse ventricular remodeling: trained immunity after myocardial infarction.

Xuanchun Huang, Lanshuo Hu, Xinxin Shi, Chengzhi Hou, Min Zhu.

  Myocardial infarction [MI] triggers a sterile inflammatory response that is essential for necrotic-tissue clearance and scar formation and should normally subside as repair progresses. In a subset of patients, however, persistent myeloid activation accompanies progressive fibrosis, ventricular dilatation, and adverse remodeling long after the acute insult. Trained immunity may help explain this temporal mismatch by allowing myocardial injury to leave a durable functional bias in innate immune cells or their hematopoietic progenitors. Damage-associated molecular patterns, inflammatory cytokines, and sympathetic signals released after MI may reprogram bone-marrow hematopoiesis through metabolic and epigenetic mechanisms. Bone-marrow-derived cells can enter the circulation and injured myocardium directly; the spleen may provide an additional reservoir, hematopoietic niche, and amplification or deployment compartment rather than an obligatory intermediate. Resident and recruited cardiac macrophages then interpret this systemic input within the heart, where macrophage-fibroblast-extracellular matrix interactions influence scar composition, remote-zone fibrosis, ventricular geometry, and progression toward heart failure. This review follows a heart-hematopoietic-heart network and distinguishes direct MI-trained-immunity evidence from MI-specific bridging evidence, adjacent trained-immunity models, and downstream remodeling evidence. Individual components are supported to different degrees, but causal continuity from MI-induced hematopoietic memory to adverse ventricular remodeling has not yet been demonstrated. Defining where durable memory is established, how myeloid output reaches the heart, and when it becomes maladaptive may support phase-specific interventions that preserve early repair while limiting later inflammation and fibrosis.

Keywords:  cardiac fibrosis; cardiac remodeling; epigenetic reprogramming; immunometabolism; macrophage–fibroblast crosstalk; myocardial infarction; sterile inflammation; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2026.1962412
Cytokine Growth Factor Rev. 2026 Oct 06. pii: S1359-6101(26)00080-8. [Epub ahead of print]92 101533

Programming innate immune memory: The context-dependent role of type I interferons.

Zhigang Rao, Theresa Neuper, Andreas Völkerer, Jutta Horejs-Hoeck.

  Type I interferons (IFNs) are best known for driving antiviral defense; however, a growing body of evidence identifies a pivotal role for type I IFNs in the establishment of innate immune memory. Depending on the nature of the priming stimulus, the identity of the responding cell, and the tissue microenvironment, type I IFN signaling may contribute to both trained immunity and tolerance. This review summarizes recent advances in identifying the molecular mechanisms by which the two best studied type I IFN family members, IFNα and IFNβ, contribute to innate immune memory. Stimuli triggering type I IFN expression range from microbial products and vaccines to inflammatory diseases, and result in reprogramming of hematopoietic stem and progenitor cells, monocytes/macrophages, dendritic cells and neutrophils. Mechanistically, type I IFNs contribute to the establishment of innate memory by remodeling chromatin accessibility and histone marks, reshaping metabolic pathways such as glycolysis, oxidative phosphorylation, lipid- and iron metabolism, and by reprogramming hematopoiesis and granulopoiesis. These effects provoke long-term immune adaptations in target cells that enhance or weaken their response to a subsequent challenge. We delineate parameters that contribute to the induction of trained immunity or tolerance and discuss potential translational implications. Ultimately, rigorous trials should test whether precise inhibition or exploitation of type I IFN signaling benefits patients by inducing or suppressing IFN-mediated innate immune memory, then using this context-specific framework to guide drug design, treatments and therapeutic endpoints.

Keywords:  Epigenetic remodeling; Immunometabolic rewiring; Innate immune memory; Tolerance; Trained immunity; Type I interferon

DOI:  https://doi.org/10.1016/j.cytogfr.2026.101533
Cells. 2026 Sep 26. pii: 1756. [Epub ahead of print]15(19):

Damage-Associated Molecular Patterns and Trained Immunity of Monocyte-Macrophage Populations in Osteoarthritis: Potential Molecular Links and Therapeutic Opportunities.

Jian Zhang, Bingbing Chen, Yundong Xu, Heguo Yan, Niqin Xiao, Jing Xie, Zhaohu Xie, Zhaofu Li.

  Osteoarthritis (OA) is now widely discussed as a whole-joint immunometabolic disease involving cartilage, synovium, and subchondral bone, rather than as cartilage degeneration driven only by mechanical stress. Tissue injury, cell death, mitochondrial dysfunction, and extracellular matrix degradation can lead to the persistent release of damage-associated molecular patterns (DAMPs), which activate innate immune responses through pattern recognition receptors (PRRs). A key unresolved issue is why inflammation can persist or recur when there is no continuous external stimulus. Trained immunity provides an emerging framework for approaching this problem, with initial direct evidence now available in circulating monocytes from knee OA but broader validation still lacking. Following an initial stimulus and a subsequent resting interval, monocytes and macrophages may retain epigenetic and metabolic alterations that modify their responses to later homologous or heterologous challenges. This review summarizes the sources of DAMPs and their recognition mechanisms in the OA microenvironment, with particular attention to their potential links with trained immunity in monocyte-macrophage populations. We discuss PRR-mediated changes in chromatin accessibility, histone modifications, DNA methylation, and non-coding RNA regulation, as well as immunometabolic events such as enhanced glycolysis, tricarboxylic acid cycle remodeling, mitochondrial dysfunction, and accumulation of key metabolites. We also examine how monocyte-macrophage populations with persistent hyperresponsiveness after stimulus withdrawal and restimulation may contribute to persistent synovitis, cartilage matrix degradation, and abnormal subchondral bone remodeling. Finally, we summarize therapeutic opportunities potentially relevant to the proposed links between DAMP signaling and trained immunity. Recent evidence that high-mobility group box 1 (HMGB1) primes a trained phenotype in circulating monocytes provides initial direct support for DAMP-associated trained immunity in knee OA. However, its generalizability across independent cohorts, other DAMP classes, myeloid-cell compartments, disease stages, and OA phenotypes remains to be established.

Keywords:  damage-associated molecular patterns; epigenetic reprogramming; metabolic reprogramming; monocyte–macrophage populations; osteoarthritis; pattern recognition receptors; trained immunity

DOI:  https://doi.org/10.3390/cells15191756
Front Immunol. 2026 ;17 1962766

Inflammatory memory as a potential driver of rosacea pathogenesis: integrating mechanisms of chronic relapse and perspectives on disease modification.

Ming Zhang, Zhou Zhou, Dandan Zhan, Yumeng Yang, Min Li.

  Inflammatory memory refers to functional changes retained by a tissue after an inflammatory episode that allow faster or stronger responses to subsequent challenges. It encompasses epigenetic memory in epithelial and stem cells, trained immunity, and tissue-resident memory T cells. Rosacea is a chronic inflammatory skin disease characterized by recurrent flushing, persistent erythema, and papulopustular lesions, and relapse after treatment cessation is common; the mechanisms that drive recurrence remain unclear. In this hypothesis-generating critical review, we use inflammatory memory as an integrative framework and examine evidence consistent with inflammatory memory in rosacea, including the Toll-like receptor 2/kallikrein-related peptidase 5/cathelicidin antimicrobial peptide (LL-37) positive feedback axis, mast-cell-mediated amplification, neuroimmune amplification, and an interleukin-1β-centered persistent inflammatory program. We draw on mechanistic evidence from psoriasis and atopic dermatitis related to tissue-resident memory T cells, epithelial memory, and trained immunity, while explicitly separating established rosacea-specific observations from indirect cross-disease parallels and speculative claims. A multilayer memory network model is proposed in which repeated triggers write memory and lower the relapse threshold; disease modification is then discussed as a candidate therapeutic goal, together with potential strategies and testable hypotheses. Direct molecular evidence for inflammatory memory in rosacea is still lacking, alternative mechanisms remain plausible, and disease modification should be viewed as a perspective rather than an established endpoint.

Keywords:  disease modification; epithelial memory; inflammatory memory; relapse threshold; rosacea; tissue-resident memory T cells; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2026.1962766
Mucosal Immunol. 2026 Oct 12. pii: S1933-0219(26)00113-3. [Epub ahead of print] 100411

Allergen-induced trained immunity in alveolar macrophages predisposes to long-lasting airway hypersensitivity.

Lin Tong, Wenjun Song, Lin Su, Mengyao Li, Jing He, Lingman Dai, Huihan Li, Xiling Wu, Qiannan Zhao, Xiaodie Shen, Yuanyuan Zhang, Yushi Yao, Qingqing Wang, Zhimin Chen.

  Allergic asthma is characterized by airway hypersensitivity to various allergens and chronic airway inflammation. The mechanisms underlying such a prolonged and broad-responsive airway hypersensitivity remain not fully understood. In this study, we systematically investigated the role of allergen-induced trained immunity in tissue resident alveolar macrophages (AMs) and its impact on long-lasting airway hypersensitivity. Here, we utilized flow cytometry and single-cell transcriptomics to analyze immune cell dynamics in murine asthma model, and we compare the differences between allergen-experienced AMs and naïve AMs. Specifically, we introduce and delve into the concept of allergen-induced trained immunity within these particular cells (Trained alveolar macrophages, Tr-AMs). Our findings demonstrated that Tr-AMs preferentially produce pro-eosinophilic chemokines upon subsequent allergen exposure and, therefore, induce exacerbated eosinophilic inflammation in the lung. The induction of Tr-AMs was potentially associated with their interactions with other immune cells, such as natural killer cells, dendritic cells, and Th2 cells. Both IFN-γ and IL-4 are critical for AM activation, we found that their simultaneous action on AMs induced the development of an MHCII+ CD206+ Tr-AM phenotype, which was specialized in producing pro-eosinophilic chemokines, including CCL24 (eotaxin-2) and CCL5 (RANTES). This study highlights the establishment and roles of Tr-AMs in pro-asthmatic airway hypersensitivity, providing a new understanding of the pathogenesis and recurrence of allergic asthma.

Keywords:  Alveolar macrophages; Asthma; Eosinophilic inflammation; IFN-γ; IL-4; Trained immunity

DOI:  https://doi.org/10.1016/j.mucimm.2026.100411
Stem Cell Reports. 2026 Oct 15. pii: S2213-6711(26)00329-2. [Epub ahead of print] 103118

Perinatal nicotine exposure disrupts hematopoietic stem cell development and elevates influenza severity in adulthood.

M G E Rommel, T Cool, A Rodriguez Y Baena, S Saini, P Medina, C Mattingly, E Bachinsky, S Chattopadhyaya, B A Manso, S Rajendiran, A K Worthington, D M Poscablo, A Deguzman, P Q Wimer, I M Voelker, T Berger-Cahn, L Langroudi, A F Svendsen, A Shariati, S Carpenter, D F Boyd, E C Forsberg.

  Developmental exposures profoundly shape lifelong health by altering disease resilience later in life. One potential cause of increased disease susceptibility is an altered immune system, originating in epigenetically maladaptive hematopoietic stem cells (HSCs). Here, we establish perinatal nicotine exposure (PNE) as a mouse model of developmental maladaptive immunity, wherein early-life environmental insults permanently alter HSCs. We show that PNE selectively disrupts the establishment of HSCs and tissue-resident, but not circulating, immune cells. Remarkably, the specific decrease of HSCs and lung-resident immune cells persists into adulthood. Single-cell transcriptomics revealed durable molecular reprogramming of adult PNE HSCs, with inverse regulation of positive trained immunity signatures. Functionally, adult PNE offspring challenged with respiratory virus exhibit exacerbated immune maladaptation, marked by increased weight loss, deteriorated lung pathology, hyper-permeability of pulmonary vasculature, tissue-resident macrophage depletion, and exaggerated neutrophil recruitment. Together, our findings establish that PNE imprints durable maladaptive immunity involving changes in HSCs and their progeny, suggesting a hematopoietic origin for the PNE-induced respiratory vulnerability.

Keywords:  fetal and neonatal hematopoiesis; hematopoietic stem cell; influenza A virus infection; maldapative trained immunity; maternal smoking; perinatal nicotine exposure; respiratory disease susceptibility and severity; tissue-resident macrophages; transcriptional memory

DOI:  https://doi.org/10.1016/j.stemcr.2026.103118
Eur J Pharmacol. 2026 Oct 16. pii: S0014-2999(26)00925-8. [Epub ahead of print] 179443

Isorhapontigenin alleviates sepsis-induced acute lung injury by targeting the RAF1-ERK1/2-CXCL10 axis to inhibit CXCR3+ neutrophil recruitment.

Ao-Lin Jiang, Chang Sun, Dong-Rong Luo, Yu-Ying Liang, Zheng Qin, Wan-Ying Zhang, Ze-Hui Jiang, Meng-Ru Wang, Hai-Hua Luo, Bing-Wen Zhu, Yi-Bai Qu, Lei Li, Yong Jiang.

  Sepsis is a life-threatening organ dysfunction syndrome resulting from a dysregulated host response to infection and is characterized by persistent hyperinflammation followed by immunosuppression. Isorhapontigenin (ISO), a natural stilbene derivative found in Chinese herbs and grapes, possesses potent antioxidant and anti-inflammatory properties; however, its potential therapeutic role in sepsis remains unclear. In this study, we investigated the protective effects of ISO against sepsis-induced multi-organ injury and the underlying molecular mechanisms. Using a murine model of sepsis, we observed that ISO administration considerably suppressed the expression of the pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor-α in the tissues. Furthermore, ISO treatment markedly improved survival rates and attenuated pathological damage in the liver and lung. Transcriptomic profiling revealed that ISO confers protection by modulating inflammatory cascades and inhibiting chemokine-mediated immune cell migration. Notably, C-X-C motif chemokine ligand 10 (CXCL10) was identified as a key hub gene. Mechanistically, ISO directly binds to RAF proto-oncogene serine/threonine-protein kinase (RAF1) and inhibits the RAF1-extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway, thereby downregulating CXCL10 expression and preventing excessive infiltration of C-X-C motif chemokine receptor 3-positive (CXCR3+) neutrophils into pulmonary tissue. In conclusion, our findings demonstrate that ISO mitigates sepsis-induced lung injury via the RAF1/ERK1/2/CXCL10 axis, providing a potential mechanistic basis for further investigation of ISO as a therapeutic candidate for sepsis.

Keywords:  CXCL10; CXCR3(+) neutrophils; Inflammation; Isorhapontigenin; RAF1; Sepsis

DOI:  https://doi.org/10.1016/j.ejphar.2026.179443
Nat Immunol. 2026 Oct 13.

Author Correction: Monocyte-derived galectin-1hi cells provide innate immune help in the generation of functional memory CD8+ T cells.

Kihong Lim, Ankit Dahal, Xiurui Lv, Kyun-Do Kim, Blake A Evans, Herman Li, Laurie A Steiner, Minsoo Kim.

DOI: https://doi.org/10.1038/s41590-026-02704-2
Gut Microbes. 2026 Dec 31. 18(1): 2748132

A helminth-microbiota metabolic relay promotes disease tolerance.

Ruohang Sun, Yi Liu, Yang Wang, Nuo Xu, Xiaoxiao Ma, Qingbo Lv, Xiufeng Zhao, Pascal Boireau, Zeming Wu, Mingyuan Liu, Xiaolei Liu, Xuemin Jin.

  Persistent infection by helminths requires limiting inflammatory damage despite incomplete pathogen clearance, yet how helminths mobilize resident microbiota to establish this state remains unclear. Here we identify a cross-kingdom metabolic relay through which Trichinella spiralis promotes systemic disease tolerance. Infection selectively expanded Ligilactobacillus murinus and redirected microbial tryptophan metabolism toward indole-3-lactic acid (ILA), a direct ligand of the aryl hydrocarbon receptor (AhR). Antibiotic perturbation abrogated ILA production, AhR activation and Treg-Th17 remodeling, whereas transfer of helminth-conditioned fecal preparations or supplementation with L. murinus or ILA restored these responses. Pharmacological inhibition or genetic deletion of AhR eliminated the protection conferred by T. spiralis, L. murinus and ILA against endotoxin-induced lung injury. In lethal SARS-CoV-2 infection, oral ILA improved survival and limited pulmonary immunopathology without reducing viral burden, thereby uncoupling host protection from pathogen control. In a human COVID-19 cohort, ILA relative abundance remained inversely associated with IFN-γ after adjustment for available clinical covariates. These findings reveal that helminths can reprogram commensal metabolism to govern systemic immune tolerance and identify microbial ILA production as a tractable postbiotic strategy for limiting inflammatory tissue damage.

Keywords:  AhR; ILA; Treg/Th17; Trichinella spiralis; gut microbiota

DOI:  https://doi.org/10.1080/19490976.2026.2748132
J Exp Med. 2026 Nov 02. pii: e20260939. [Epub ahead of print]223(11):

Macrophages as programmable integrators of disease tolerance across lifespan.

Dmitry V Bulavin.

Clinical outcome may depend as much on the host's ability to preserve tissue function as on its ability to eliminate pathogens. The former reflects disease tolerance, with macrophages emerging as programmable integrators of multicellular tolerance networks. These networks are progressively reconfigured with age, altering the balance between tissue-protective and pathological responses, while mRNA vaccines and modulation of MDA5 signaling may offer clinically translatable means of transiently engaging these pathways.

DOI: https://doi.org/10.1084/jem.20260939
Shock. 2026 Oct 13.

Opsonic Peptide MOP3 Attenuates Ischemic Acute Kidney Injury.

Megan Tenet, Hui Jin, Monowar Aziz, Ping Wang.

   BACKGROUND: Renal ischemia/reperfusion (I/R) induced acute kidney injury (AKI) is a common and serious condition characterized by renal dysfunction, inflammation, tubular injury, and cell death. Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern that contributes to inflammation and tissue injury. MFG-E8-derived oligopeptide 3 (MOP3) is an opsonic peptide that binds eCIRP and promotes its phagocytic clearance. Here, we investigated the therapeutic effects of MOP3 in a murine model of renal I/R-induced AKI.
METHODS: Mice were subjected to 30 minutes of bilateral renal ischemia and treated with MOP3 or vehicle at the onset of reperfusion. Blood and kidney tissues were collected 20 h later. Renal inflammation, kidney function, tubular injury markers, histological damage, and cell death were assessed by RT-qPCR, biochemical assays, Western blotting, hematoxylin and eosin staining, and TUNEL staining.
RESULTS: MOP3 treatment reduced circulating eCIRP by 40% and renal IL-6, IL-1β, MIP-2, and KC mRNA expression by 43%, 84%, 73%, and 69%, respectively, compared with vehicle treatment. Serum urea nitrogen, creatinine, and NGAL levels were reduced by 56%, 63%, and 44%, respectively, after MOP3 treatment. MOP3 also decreased renal KIM-1 and NGAL mRNA expression by 88% and 44% and reduced their protein levels by 29% and 45%, respectively. Furthermore, MOP3 attenuated renal tubular injury and decreased TUNEL-positive cells.
CONCLUSIONS: These findings demonstrate that MOP3 attenuates inflammation, renal dysfunction, tubular injury, and cell death following renal I/R, suggesting that MOP3 may represent a promising therapeutic strategy for ischemic AKI.

Keywords:  Acute kidney injury; Extracellular CIRP; Inflammation; MOP3; Renal ischemia/reperfusion

DOI:  https://doi.org/10.1097/SHK.0000000000002949
Brain Behav Immun. 2026 Oct 14. pii: S0889-1591(26)00810-X. [Epub ahead of print] 107062

Early post-sepsis innate behavioral changes in aged mice occur independently of detectable neuroinflammation.

Han Noo Ri Lee, Jason Lin, Brandon Baer, Anisa Haffizulla, Lorraine B Ware, Fiona E Harrison, Julie A Bastarache.

   BACKGROUND: Sepsis disproportionately causes long-term cognitive and functional impairments in elderly survivors, including deficits in activities of daily living and functional independence. The neurobiological mechanisms driving this vulnerability in the aged brain remain poorly understood. We tested whether the aged brain possesses a unique vulnerability to sepsis-induced impairment in the early post-acute recovery period.
METHODS: Polymicrobial sepsis was induced in young (3-months) and aged (18-months) mice via cecal slurry injection, with dosing adjusted for comparable acute illness severity. Behavioral assessments (learning, memory, locomotion, innate behaviors) were performed through Day 7 post-infection. On Day 8, brains were analyzed for inflammatory cytokines, glial activation, neuronal protein expression, and blood-brain barrier (BBB) permeability.
RESULTS: Aged septic mice exhibited alterations in nest building and sociability, whereas young mice with comparable illness severity remained behaviorally resilient. The behavioral changes in aged mice occurred in the absence of broad systemic or neuroinflammation. Conversely, young septic mice maintained normal behavior despite significantly elevated systemic and neuroinflammation. Aged mice displayed signs of glial activation, neuronal protein modulation, and BBB permeability compared to young mice, but sepsis did not significantly exacerbate these markers in either group.
CONCLUSION: Our findings demonstrate an age-dependent divergence in neurologic recovery after sepsis: while young mice exhibit behavioral resilience despite systemic and neuroinflammation, aged mice display alterations in innate behavior that are present even after the apparent resolution of acute illness. This suggests that the changes in innate behavior in the aged mice are not driven solely by sepsis-induced inflammation, but rather by a cumulative burden of age-related vulnerabilities, including microglial priming, astrocytic activation, and increased BBB permeability, that render aged brains unable to compensate for a severe acute physiological challenge.

Keywords:  Age-dependent vulnerability; Behavioral resilience; Blood-brain barrier permeability; Functional decline; Innate behaviour; Microglial activation; Neuroinflammation; Polymicrobial sepsis model; Post-sepsis recovery; Sepsis-associated encephalopathy

DOI:  https://doi.org/10.1016/j.bbi.2026.107062
Cell Death Differ. 2026 Oct 14.

USP25 augments XIAP-mediated signaling to safeguard intestinal homeostasis.

Jiangyun Shen, Deyu Deng, Deqi Wang, Jianzhao Zhang, Yimin Lin, Liyan Lou, Yanqi Xu, Lili Ma, Zijun Cao, Keshuo Jin, Fuqi Mei, Jiaqing Chen, Jun Xu, Wenhua Zheng, Jing Ruan, Yangping Shentu, Xu Wang.

Nucleotide-binding oligomerization domain containing 2 (NOD2) recognizes conserved bacterial components in the cytoplasm to initiate innate immune responses, and its mutations are closely associated with Crohn's disease (CD). Here, we discover that the NOD2 signaling is regulated by the deubiquitinase USP25. Macrophages lacking USP25 exhibit impaired NOD2 signaling and are defective in cytokine production upon stimulation with muramyl dipeptide (MDP). USP25 enhances NOD2-initiated signal transduction by increasing the expression and recruitment of X-linked inhibitor of apoptosis protein (XIAP). In mice, USP25 deficiency exacerbates intestinal inflammation induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS), whereas USP25 overexpression alleviates TNBS-induced colitis. Moreover, USP25 deficiency leads to spontaneous intestinal inflammation in aged mice. Importantly, a known single nucleotide polymorphism associated with human inflammatory bowel disease compromises USP25 expression, and lower USP25 expression is detected in patients with CD. Thus, USP25 plays a critical role in NOD2 signaling and may represent a potential therapeutic target for CD.

DOI: https://doi.org/10.1038/s41418-026-01885-5
Immunity. 2026 Oct 16. pii: S1074-7613(26)00390-0. [Epub ahead of print]

Embracing macrophage complexity for research and translation.

Florent Ginhoux, Kevin Mulder, Sebastian Arcila-Barrera, Ido Amit.

  Macrophages are among the most versatile differentiated cell types in the body, serving as key regulators of tissue development, homeostasis, inflammation, repair, and immunity. Their functional diversity cannot be captured by fixed subsets, binary activation states, or single-marker definitions. Macrophage identity emerges instead from the integration of developmental origin, tissue niche, epigenetic history, local environmental cues, and disease-associated signals. Advances in single-cell genomics, spatial profiling, epigenomics, in vivo perturbation, and computational modeling now show that this behavior is organized through modular gene programs, so that any given macrophage state is best described as a weighted combination of program activities rather than a discrete label. We argue that embracing this modular architecture matters not only for annotation but for therapy: macrophage-directed interventions will require defining disease-associated states, identifying surface-accessible entry points into them, and rewiring the underlying programs with spatial and temporal precision.

Keywords:  immune plasticity; immunotherapy; macrophage; macrophage reprogramming; macrophage-targeted therapies; modular gene programs; single-cell genomics; synthetic immunology; tissue microenvironment; translational immunology

DOI:  https://doi.org/10.1016/j.immuni.2026.09.015