bims-traimu Biomed News
on Trained immunity
Issue of 2026–03–08
thirteen papers selected by
Yantong Wan, Southern Medical University
  1. Trained immunity in neuroinflammation: emerging evidence, clinical perspectives, and future directions.
  2. Editorial: From Trained Immunity to Rheumatic Diseases: Updated Evidence.
  3. Training the Lung, Taming the NETs.
  4. Identification of MTURN as a trained immunity-related biomarker for heart failure via integrative transcriptomic machine learning analysis and experimental validation.
  5. Host-focused immunity, metabolism, and diagnostic innovation for precision control of tuberculosis globally.
  6. Long-term inhibition of protease hypersensitivity by initial immunological cross-regulation and epigenetic memory in lung stromal cells.
  7. Cross-talk between lipopolysaccharide tolerance and AGEs in the regulation of macrophage inflammation and cholesterol efflux.
  8. Toll-like receptor signaling outcome is determined by the stoichiometry of the endogenous TRIFosome.
  9. Type 2 diabetes impairs macrophage antimicrobial capability and increases susceptibility to sepsis.
  10. Exclusion of Notch from the contact site during efferocytosis restricts anticancer immunity.
  11. α-Ketoglutarate protects against cartilage damage via epigenetically driven metabolic reprogramming in osteoarthritis models.
  12. Thromboxane receptor activation in dendritic cells mitigates sepsis by suppressing S100a8/a9-mediated neutrophil recruitment.
  13. Predicting Macrophage Spatial Localization from Single-Cell Transcriptomes to Uncover Disease Mechanisms.
  1. Neuroscience. 2026 Mar 03. pii: S0306-4522(26)00156-9. [Epub ahead of print]
    Trained immunity in neuroinflammation: emerging evidence, clinical perspectives, and future directions.
    Enis Guso, Alessia Lupoli, Emanuele Olivieri, Alessia Bottoni, Maira Gironi, Davide M Missarelli, Ahmed T Toosy, Elena Rossi, Roberto Furlan.
      Trained immunity is the ability of the innate immune system to mount a heightened response to an environmental stimulus after a previous encounter with a noxious trigger. This effect is mediated by metabolic rewiring and epigenetic reprogramming in innate immune cells. In the context of neuroinflammation, trained immunity may represent a major contributor to the pathogenesis of neurological diseases, exerting both detrimental and potentially beneficial effects. While the general mechanisms and systemic implications of trained immunity are widely discussed, evidence in central nervous system (CNS) diseases remains fragmented and largely confined to individual pathological conditions. As a result, a comprehensive framework integrating these findings and identifying shared mechanisms across neurological disorders is still lacking. In this review, we explore the concept of trained immunity with a focus on neuroinflammatory and neurodegenerative diseases, synthetizing evidence from multiple CNS pathologies, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, and cerebrovascular disorders. We first critically examine preclinical and experimental studies addressing innate immune memory in the CNS and subsequently integrate these findings with emerging clinical evidence, aiming to identify convergent mechanisms and disease-relevant immune memory signatures. Finally, we discuss potential therapeutic targets identified in preclinical settings and outline key unresolved issues, including the nature of triggering stimuli, thresholds, and temporal dynamics shaping innate immune memory in the CNS. By highlighting current limitations and defining critical questions for future research, this review presents a unifying perspective on trained immunity in neurological diseases and underscores the translational potential to modulate neuroinflammation and to influence disease progression.
    Keywords:  Cell metabolism; Epigenetic remodelling; Innate immune memory; Ischemic stroke; Neurodegeneration; Neuroimmunology; Neuroinflammation; Trained immunity
    DOI:  https://doi.org/10.1016/j.neuroscience.2026.02.047
  2. Int J Rheum Dis. 2026 Mar;29(3): e70484
    Editorial: From Trained Immunity to Rheumatic Diseases: Updated Evidence.
    Kuan-Chi Chen, Yu-Hao Huang, Ya-An Tsai, Po-Cheng Shih, Su-Boon Yong, Chin-Yuan Yii.
      
    DOI:  https://doi.org/10.1111/1756-185x.70484
  3. Front Cell Infect Microbiol. 2026 ;16 1778635
    Training the Lung, Taming the NETs.
    Piyush Baindara.
      Respiratory infections remain a major global health threat, and recent epidemics have shown that treating the pathogen alone is not enough. In severe influenza, COVID-19, RSV, and bacterial pneumonia, lung failure often results less from microbial load and more from the host's overactive immune response. Two key processes, neutrophil extracellular traps (NETs) and trained immunity, sit at the center of this shift toward host-focused intervention. Although both are innate defenses, they are usually discussed in isolation: NETs in the context of acute inflammation and thrombosis, and trained immunity in the context of vaccines, epigenetic reprogramming, and metabolic adaptation. Yet in the lung, these mechanisms function as interconnected elements of early defense. This editorial argues that effective therapies should no longer treat them as separate phenomena but instead co-target NET regulation and trained-immunity pathways as a unified, host-directed strategy to reduce immunopathology and improve outcomes in severe respiratory infections.
    Keywords:  NEtosis; host-directed therapies; infection; inflammation; trained-immunity
    DOI:  https://doi.org/10.3389/fcimb.2026.1778635
  4. Front Immunol. 2026 ;17 1739660
    Identification of MTURN as a trained immunity-related biomarker for heart failure via integrative transcriptomic machine learning analysis and experimental validation.
    Tianyuan Yang, Zhixin Li, Mingliang Pan, Xiaohong Wang, Wei Huang, Nebahat Ece Kesten, Tianqing Peng, Guo-Chang Fan.
       Background: Heart failure (HF) is a global health burden marked by high morbidity and limited treatment efficacy across subtypes. The lack of reliable molecular biomarkers for heart failure impedes personalized therapy. Emerging evidence suggests that macrophage-trained immunity drives chronic inflammation and cardiac remodeling, highlighting immune-related genes as promising biomarkers.
    Methods: We integrated transcriptomic data from five independent HF cohorts and one macrophage-trained immunity model. Differentially expressed genes (DEGs) analysis, weighted gene co-expression network analysis (WGCNA), immune infiltration profiling, and six machine-learning algorithms were applied to screen immune-related candidate genes. Functional relevance was assessed by gene set enrichment analysis (GSEA) and single-cell RNA-seq of human cardiac tissue. Finally, we established a THP-1-derived macrophage trained immunity model to validate the paracrine effects of macrophage Maturin (MTURN) and Piezo-type mechanosensitive ion channel component 1 (PIEZO1) in cardiomyocytes.
    Results: Seven hub genes were identified from HF-DEGs, the trained immunity transcriptional signature, and WGCNA co-expression modules. Among them, MTURN, an evolutionarily conserved regulator of differentiation and inflammation, emerged as the most robust candidate, showing consistent upregulation in HF samples across all cohorts with superior diagnostic performance. Importantly, GSEA linked MTURN to innate immune activation and adhesion/signaling pathways. Single-cell RNA-seq analyses of human cardiac tissue revealed MTURN enrichment in cardiac macrophages with a progressive increase along pseudotime. Experimentally, trained immunity macrophages displayed an elevation of glycolytic and inflammatory markers together with increased MTURN and PIEZO1. Accordingly, the conditioned medium collected from such trained macrophages could upregulate expression of HF markers (i.e., NPPA/B) in AC16 cardiomyocytes.
    Conclusion: Multi-cohort, single-cell RNA-seq, and experimental data collectively suggest MTURN as a trained immunity-related biomarker for the diagnosis of heart failure with a potential link to PIEZO1-mediated cardiac remodeling.
    Keywords:  MTURN; biomarker; heart failure; machine learning; trained immunity
    DOI:  https://doi.org/10.3389/fimmu.2026.1739660
  5. Life Sci. 2026 Mar 03. pii: S0024-3205(26)00122-0. [Epub ahead of print] 124313
    Host-focused immunity, metabolism, and diagnostic innovation for precision control of tuberculosis globally.
    Isil Aksan Kurnaz, Ekin Sonmez, Augustine Ovie Edegbene, Gergely Toldi, Muhammad Qasim, Suraj Bhattarai, Shymaa Enany.
      Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains one of the deadliest infectious diseases worldwide. Despite advances in treatment and diagnostics, challenges such as multidrug resistance, inadequate vaccines, diagnostic gaps and health inequities continue to impede global control efforts. This review explores emerging insights into host-pathogen interactions, with emphasis on host-directed interventions, trained innate immunity, and immunometabolic reprogramming of TB as complementary approaches. We highlighted advances in rapid and point-of-care diagnostics, including nucleic acid amplification, transcriptomic, proteomic and metabolomic biomarkers, breath-omics, and smartphone-integrated monitoring tools. Furthermore, we discussed multi-omics integration and artificial intelligence (AI) approaches that offer transformative potential for biomarker discovery, patient stratification, and personalized therapy. By shifting the focus from pathogen elimination to host resilience, we emphasized the importance of interdisciplinary collaboration and innovation in accelerating TB elimination globally. Our findings call for a host-inclusive framework to strengthen global TB control, enhance equity, and translate cutting-edge science into field-ready applications.
    Keywords:  Artificial intelligence; Biomarkers; Diagnostics; Host-directed therapy; Immunometabolism; Multi-omics; Trained immunity; Tuberculosis
    DOI:  https://doi.org/10.1016/j.lfs.2026.124313
  6. Nat Immunol. 2026 Mar 03.
    Long-term inhibition of protease hypersensitivity by initial immunological cross-regulation and epigenetic memory in lung stromal cells.
    Jaechan Ryu, Amy Blondeau, Olivier Mirabeau, Selene Di Carlo, Victoire Baillet, David Hardy, Christian Pasquali, Lucie Peduto, Gérard Eberl.
      Prevention and regulation of excessive inflammation is a key target to protect against inflammatory pathologies such as autoimmunity and allergy. In a mouse model of acute lung protease hypersensitivity, we assessed the efficacy of immunological cross-regulation to mitigate pathogenic inflammation. We show that induction of a type 1 response using Toll-like receptor ligands or a bacterial lysate efficiently blocks acute eosinophilia and type 2 responses evoked by the cysteine protease papain. Upon rechallenge with papain weeks later, mice displayed enhanced type 2 responses and eosinophilia, whereas this response was absent if the initial inflammation was cross-regulated. Memory of the initial event was stored in adventitial stromal cells expressing CCL11. Accessibility of the Ccl11 locus was increased by papain exposure in an interleukin-4- and interleukin-13-dependent manner and blocked by interferon gamma. Our results show how the nature of an initial inflammation is memorized by tissue-resident cells and shapes subsequent inflammatory responses.
    DOI:  https://doi.org/10.1038/s41590-026-02439-0
  7. Front Immunol. 2026 ;17 1669028
    Cross-talk between lipopolysaccharide tolerance and AGEs in the regulation of macrophage inflammation and cholesterol efflux.
    Danielle Ribeiro Santos, Monique de Fatima Mello Santana, Eduarda Palanca, Milena Gomes Vancini, Sayonara Ivana Santos de Assis, Aritania Sousa Santos, Denise Frediani Barbeiro, Suely Kunimi Kubo Ariga, Maria Lucia Correa-Giannella, Francisco Garcia Soriano, Marisa Passarelli.
       Introduction: Immune cell infiltration with high expression of receptors for advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4) promotes vascular inflammation and accelerates atherosclerosis. Advanced glycated albumin (AGE-albumin) primes macrophages for heightened inflammatory responses to lipopolysaccharide (LPS). Here, we investigated whether LPS-induced tolerance modulates AGE-driven inflammatory priming and cholesterol efflux in macrophages.
    Methods: Cholesterol-enriched bone marrow-derived macrophages (BMDMs) and RAW264.7 macrophages were subjected to LPS tolerance induction, treated with control (C)- or AGE-albumin, and rechallenged with LPS. In parallel, LPS tolerance was induced in vivo by repeated low-dose LPS injections, followed by BMDM differentiation, cholesterol loading, albumin treatments, and secondary LPS stimulation. Tumor necrosis factor (TNF) secretion was assessed by ELISA, gene expression by RT-qPCR, and HDL-mediated ¹4C-cholesterol efflux using conditioned media or direct HDL incubation.
    Results: In BMDMs, LPS tolerance reduced TNF secretion following C-albumin treatment but not AGE-albumin. In RAW264.7 macrophages, TNF secretion was reduced by 53% and 77.6% after C- and AGE-albumin treatment, respectively. BMDMs from LPS-tolerant mice exhibited reduced TNF secretion following both albumin treatments. Gene expression analysis revealed that AGE-albumin selectively increased Ager and Tlr4 expression in tolerant BMDMs, whereas C-albumin was associated with broad suppression of pro-inflammatory genes. Conditioned media from tolerant BMDMs markedly enhanced HDL-mediated cholesterol efflux in naïve macrophages, while direct exposure of tolerant BMDMs to AGE-albumin reduced HDL-mediated efflux by 40%.
    Discussion: These findings demonstrate that LPS tolerance promotes an atheroprotective macrophage phenotype characterized by attenuated inflammatory signaling and enhanced cholesterol efflux. However, this protective immunometabolic program is selectively disrupted by AGE exposure, highlighting a critical interface through which chronic metabolic stress may override innate immune tolerance and contribute to atherosclerotic progression.
    Keywords:  advanced glycation; atherosclerosis; inflammation; lipopolysaccharide tolerance; macrophages
    DOI:  https://doi.org/10.3389/fimmu.2026.1669028
  8. Sci Adv. 2026 Mar 06. 12(10): eaeb9507
    Toll-like receptor signaling outcome is determined by the stoichiometry of the endogenous TRIFosome.
    Martin C Moncrieffe, Prasanna Suresh, Joe Boyle, Yuhao Cui, Bharti Nawalpuri, Brett Verstak, Yu P Zhang, Ziwei Zhang, Marcus Taylor, Edward H Egelman, Nicholas Gay, David Klenerman, Clare Bryant.
      Toll-like receptors (TLRs) drive innate immunity via assembly of macromolecular signal transduction platforms [supramolecular organizing centers (SMOCs)] coordinated by adaptor proteins such as Toll/interleukin-1 receptor (IL-1R) domain-containing adaptor-inducing interferon-β (TRIF), but whether oligomeric TRIFosomes form is unknown. Here, using cryo-electron microscopy and biophysical characterization of full-length TRIF in vitro, we show that it forms filamentous oligomers, which associate with the TRIF signaling partners receptor interacting protein 1 (RIP1) and RIP3 kinases, suggesting that oligomeric TRIFosomes could form. Endogenous TRIF, however, is predominantly monomeric in the absence of ligand, only forming TRIFosome oligomers in macrophages after stimulation of TLR4 or TLR3 when large, macromolecular signaling complexes form. TRIFosomes are fully formed 45 min after TLR3 or 60 min after TLR4 stimulation, commensurate with activation of nuclear factor κB in these cells. TLR3/4 activation triggers rapid interferon signaling prior to TRIFosome formation through monomeric TRIF, unexpectedly suggesting that a macromolecular platform of TRIF is not required to drive this signaling pathway. Collectively, these data show TRIFosome macromolecular platform formation and, unexpectedly, that TLR signaling can be SMOC-independent in addition to being SMOC-dependent.
    DOI:  https://doi.org/10.1126/sciadv.aeb9507
  9. J Immunol. 2026 Feb 09. pii: vkaf375. [Epub ahead of print]215(2):
    Type 2 diabetes impairs macrophage antimicrobial capability and increases susceptibility to sepsis.
    Mei Zhang, Yuanqing Zeng, Xingyu Li, Ningbo Deng, Yongqiang Yang, Haibo Zhou, Li Ding, Yongjian Wu, Siqi Ming.
      Sepsis remains one of the primary causes of mortality in intensive care units, with an overall death rate of approximately 20%. Type 2 diabetes (T2D) exacerbates the incidence of infections, leading to increased long-term morbidity and mortality associated with sepsis. Macrophages are critical for the defense and clearance of invading pathogens during sepsis. Nevertheless, limited research has addressed the impact of T2D on macrophage dysfunction in sepsis conditions. In this study, we observed a significant impairment in the phagocytic and intracellular bacterial killing abilities of macrophages in a T2D sepsis model. Utilizing the cecal ligation and puncture sepsis model, we revealed a reduction in tissue-resident macrophages and an elevated bacterial burden in T2D mice. Moreover, peripheral monocytes from T2D patients and peritoneal macrophages from T2D mice exhibited the dampened phagocytic and intracellular killing abilities, characterized by decreased expressions of phagocytic receptors and a diminished capacity to generate reactive oxygen species. In addition, exogenous granulocyte-macrophage colony-stimulating factor administration enhanced survival rates and reduced bacterial loads in T2D mice by restoring phagocytosis and bacterial eradication of macrophages/monocytes. Collectively, these data suggest that T2D contributes to macrophage dysfunction and impaired bacterial clearance, leading to an increased susceptibility to sepsis.
    Keywords:  bacterial clearance; macrophages; sepsis; type 2 diabetes
    DOI:  https://doi.org/10.1093/jimmun/vkaf375
  10. Nat Immunol. 2026 Mar 03.
    Exclusion of Notch from the contact site during efferocytosis restricts anticancer immunity.
    Zhenrui Li, Beisi Xu, Piyush Sharma, Cliff Guy, Emilio Boada-Romero, Katherine Verbist, Ao Guo, Luigi Mari, Suresh Poudel, Mao Yang, Douglas R Green.
      The clearance of dying cells by phagocytes (efferocytosis) is important for maintenance of tissue homeostasis and the active repression of inflammatory responses but can promote an immunosuppressive tumor microenvironment. Here we show that Notch signaling is suppressed actively during efferocytosis and that activation of this pathway by ectopic expression of the Notch intracellular domain in myeloid cells improves anticancer immunity in mice. Contact with dead cells or IgG-coated surfaces induces the activation of an integrin barrier that excludes Notch from the contact site to prevent it signaling. The formation of this active integrin barrier requires the Rubicon-VPS34 complex, which recruits phospholipase D (PLD) to regulate integrin activation. Ablation of Rubicon in the host or inhibition of PLD increases Notch activation during efferocytosis and improves anticancer immunity in a manner dependent on Notch signaling. These findings identify a regulatory mechanism that restricts Notch signaling during efferocytosis.
    DOI:  https://doi.org/10.1038/s41590-026-02452-3
  11. J Clin Invest. 2026 Mar 02. pii: e172380. [Epub ahead of print]136(5):
    α-Ketoglutarate protects against cartilage damage via epigenetically driven metabolic reprogramming in osteoarthritis models.
    Shuaijun Li, Jiefeng Huang, Ting Shang, Laiya Lu, Orion R Fan, Peisheng Jin, Xin Zou, Zixin Cai, Wuyan Lu, Shuangmeng Jia, Linxiao Li, Ke Fang, Fengting Niu, Jiaojiao Li, Cheng Zhao, Qian Wang, Ruizhu Sun, Si Shi, Feng Yin, Yun Zhang, Yi Eve Sun, Lei Cui.
      The link between glutaminolysis and osteoarthritis (OA) has only recently begun to be elucidated. Here, we report the association of obesity- and injury-induced cartilage damage with impaired glutaminolysis in chondrocytes. Defective glutaminolysis triggered the onset and progression of OA, with enhanced catabolism and decreased anabolism. Supplementation of α-ketoglutarate (αKG), a key component in glutaminolysis and an epigenetic factor, effectively protected cartilage against degradation in vivo via a TCA cycle- and HIF-1α-independent manner. Mechanistically, OA pathogenic factors increased H3K27me3 deposition on promoters of key glutaminolysis genes, including Slc1a5 and Gls1, leading to impaired glutaminolysis. Conversely, αKG facilitated Kdm6b-dependent H3K27me3 demethylation of not only glutaminolysis genes to rescue Gln metabolism but also Ube2o to reverse OA. Elevated Ube2o expression led to TRAF6 ubiquitination and subsequent inhibition of NF-κB signaling, thereby reversing the pathological reprogramming of glycolysis and oxidative phosphorylation and protecting against cartilage destruction. Collectively, these results demonstrated that OA pathogenic factors impair glutaminolysis through epigenetic regulation, which further exacerbate OA. Moreover, αKG restores metabolic homeostasis and alleviates OA through H3K27me3 demethylation.
    Keywords:  Cartilage; Inflammation; Metabolism
    DOI:  https://doi.org/10.1172/JCI172380
  12. Signal Transduct Target Ther. 2026 Mar 03. pii: 75. [Epub ahead of print]11(1):
    Thromboxane receptor activation in dendritic cells mitigates sepsis by suppressing S100a8/a9-mediated neutrophil recruitment.
    Ronglu Du, Ting Pan, Yuhan Wang, Yan Fan, Qian Liu, Xixi Tao, Shumin Guo, Danyang Tian, Roger S-Y Foo, Keliang Xie, Jie Zhou, Yujun Shen, Ying Yu.
      Dendritic cells (DCs) regulate both innate and adaptive immunity during sepsis. Prostaglandins (PGs), small lipid molecules derived from arachidonic acid via COX enzymes, are crucial regulators of immune homeostasis and inflammation. However, their role in sepsis pathogenesis remains poorly defined. In this study, we identified a significant negative correlation between DC depletion and disease severity in patients with sepsis. Thromboxane (TX) A2 receptor (TP) expression was markedly reduced in the blood DCs of patients with sepsis. Patients with low DC-TP expression presented increased blood neutrophil counts and worsened disease severity. In murine models of sepsis induced by cecal ligation and puncture and lipopolysaccharide challenge, DC-specific TP deficiency exacerbated sepsis by promoting S100a8/a9-mediated neutrophil recruitment and, subsequently, neutrophil extracellular trap (NET) formation and lung injury. Genetic and pharmacological inhibition of the S100a8/a9-TLR4 axis protected TP-deficient mice from fatal sepsis. Mechanistically, TP signaling suppressed S100a8/a9 expression in DCs via PKCδ-Stat1 signaling, thereby restricting neutrophil infiltration and NET formation. Finally, the targeted activation of TP in DCs via the nanodrug DCpep-U-46619 effectively alleviated sepsis-induced lung injury in mice. These findings establish TP as a critical immunoregulatory receptor in DCs, highlighting its potential as a therapeutic target for sepsis.
    DOI:  https://doi.org/10.1038/s41392-026-02592-w
  13. Adv Sci (Weinh). 2026 Feb 28. e10924
    Predicting Macrophage Spatial Localization from Single-Cell Transcriptomes to Uncover Disease Mechanisms.
    Junping Yin, Qi Mei, Hans-Joachim Paust, Ning Song, Yu Zhao, Daniela Klaus, Melanie Eichler, Yijun Hua, Jie Qin, Weiting Cheng, Christina K Weisheit, Veronika Lukacs-Kornek, Isis Ludwig-Portugall, Sibylle von Vietinghoff, Christian F Krebs, Johanna Klughammer, Ulf Panzer, Christian Kurts, Jian Li.
      When cells are isolated for single-cell RNA sequencing (scRNA-seq), their positional information is inevitably lost. Here, an algorithm termed MERLIN is described that can reconstruct such information in organs with compartmentalized anatomy, such as the kidney. Several independent immune cell scRNA-seq datasets from three renal compartments were generated to train different machine learning algorithms. A modified multi-layer Perceptron approach most accurately predicted positions of resident macrophages, best, achieving over 75% accuracy in both murine and human kidney datasets. More motile immune cells, like lymphocytes, were not predictable. Positional transcriptomic fingerprints were enriched in pathways of microenvironmental responses and cellular adaptation, and showed a sex bias. MERLIN also predicted positions of resident and recently recruited macrophages in a crescentic glomerulonephritis mouse model. Analysis of published scRNA-seq datasets from endotoxin- and ischemia/reperfusion-induced models of acute kidney injury revealed proinflammatory responses predominantly in outer medullary macrophages, consistent with the known pathology. Moreover, the response of cortical macrophages to commonly used therapies for diabetic nephropathy aligned with the known clinical drug efficacy. Finally, MERLIN was successfully trained to predict the spatial distribution of brain microglia. Together, MERLIN enables spatial interpretation of scRNA-seq datasets in organs with defined anatomical regions and enhances mechanistic insights into disease processes.
    Keywords:  inflammation; kidney disease; macrophages; microglia; spatial immunology
    DOI:  https://doi.org/10.1002/advs.202410924
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