bims-traimu Biomed News
on Trained immunity
Issue of 2026–11–01
twelve papers selected by
Yantong Wan, Southern Medical University
  1. Metabolic licensing of innate immune memory.
  2. From emergency myelopoiesis to trained immunity? Reframing post-stroke myeloid reprogramming along the brain-bone marrow axis.
  3. Nuclear NAD+ promotes innate immune memory by inhibiting KDM5A-dependent histone demethylation.
  4. Beyond Histocompatibility: Donor Tissue Immune States and Their Role in Heart Transplantation.
  5. Immunometabolic checkpoint: The dual regulatory role of macrophages in islet destruction in type 1 diabetes.
  6. Low-frequency parasitized cells in bone marrow alter myelopoiesis following immunization with the live attenuated Leishmania major Cen -/- vaccine.
  7. Platelet-macrophage crosstalk in cardiac inflammation and remodeling.
  8. β-Glucan Pretreatment Attenuates Single Prolonged Stress-Associated Behavioural and Neuroinflammatory Changes in Male Mice.
  9. Autophagy in macrophages curtails IL-1α-mediated immune priming against lung infections.
  10. Inflammatory memory primes the intestine for enhanced regenerative potential.
  11. Diet at disease onset determines tissue inflammatory memory.
  12. Post-acute infection: before we forget it again.
  1. Sci Immunol. 2026 Oct 30. 11(124): eaek9099
    Metabolic licensing of innate immune memory.
    Musa M Mhlanga, Andrew A Pieper.
      NAD+ is revealed to be a metabolic signal that preserves an epigenetic mark central to trained immunity by inhibiting the histone demethylase KDM5a (see related Research Article by Jin et al.).
    DOI:  https://doi.org/10.1126/sciimmunol.aek9099
  2. Front Neurol. 2026 ;17 1976078
    From emergency myelopoiesis to trained immunity? Reframing post-stroke myeloid reprogramming along the brain-bone marrow axis.
    TongZhu Wei, YongJiu Wang.
      Ischemic stroke rapidly mobilizes myeloid cells from anatomically distinct bone-marrow niches, while emerging evidence indicates that severe cerebral injury can also leave a durable imprint on hematopoiesis. These observations have encouraged the use of the term trained immunity in stroke biology, but acute myeloid expansion is not equivalent to innate immune memory. In this Mini review, we distinguish acute myeloid activation, myelopoietic responses consistent with emergency myelopoiesis, and central trained immunity involving hematopoietic stem and progenitor cells (HSPCs). We use an operational four-feature framework-persistence, progenitor involvement, epigenetic or metabolic reprogramming, and functional recall-to grade the strength of current evidence. We consider a sequential transition from emergency myelopoiesis to trained immunity as one testable possibility rather than an established pathway, while allowing for parallel or independent mechanisms. The key unresolved questions are where durable memory is stored, when acute hematopoietic adaptation becomes stabilized, and which outputs are maladaptive versus reparative. Resolving these boundaries is essential before marrow-directed immunomodulation can be translated to patients with ischemic stroke.
    Keywords:  brain-bone marrow axis; emergency myelopoiesis; hematopoietic stem and progenitor cells; ischemic stroke; neuroinflammation; skull bone marrow; trained immunity
    DOI:  https://doi.org/10.3389/fneur.2026.1976078
  3. Sci Immunol. 2026 Oct 30. 11(124): eaea5625
    Nuclear NAD+ promotes innate immune memory by inhibiting KDM5A-dependent histone demethylation.
    Huan Jin, Zining Wang, Yongxiang Liu, Zifeng Wang, Mengyun Li, Ju Xue, Yiqun Zhang, Tiantian Yu, Shoujie Wang, Bitao Huo, Chunwei Li, Xiaojuan Wang, Ruhui Yao, Huanling Zhang, Jiahong Yi, Yanxun Lin, Lei Cui, Hui Guo, Zixuan Guo, Ling Zhang, Chaoyun Pan, Xuetong Shen, Gelin Wang, Gaofeng Fan, Zhiming Wu, Jing Tan, Song Gao, Jin-Xin Bei, Peng Huang, Jinyun Liu, Xiaojun Xia.
      Trained immunity is tightly regulated by metabolic and epigenetic reprogramming, yet how these changes are orchestrated at the chromatin level to establish long-term innate immune memory is not fully understood. Here, we show that induction of trained immunity elevates nuclear levels of nicotinamide adenine dinucleotide (NAD+), which directly binds to KDM5A demethylase and inhibits its activity, thereby sustaining H3K4me3 (histone H3 lysine 4 trimethylation) levels and chromatin accessibility at inflammatory gene promoters to enhance "memory" responsiveness upon restimulation. Genetic deletion or pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ synthesis, impaired trained immunity and associated antitumor activity. Nicotinamide mononucleotide (NMN) supplementation rescued defective trained immunity-mediated antitumor activity in NAMPT-deficient and aged mice. In human cancer, NAMPT expression in myeloid cells correlated with an inflammatory tumor microenvironment. Our findings identify KDM5A as a nuclear NAD+ sensor that orchestrates histone methylation and chromatin accessibility required for trained immunity.
    DOI:  https://doi.org/10.1126/sciimmunol.aea5625
  4. Int J Mol Sci. 2026 Oct 10. pii: 8985. [Epub ahead of print]27(20):
    Beyond Histocompatibility: Donor Tissue Immune States and Their Role in Heart Transplantation.
    Tomasz Urbanowicz, Mariusz Kowalewski, Piotr Suwalski, Giuseppe Maria Raffa.
      Heart transplantation transfers not only donor alloantigens and functional myocardium but also a pre-existing tissue environment shaped by resident immune, vascular, stromal, and parenchymal populations. This review examines the hypothesis that the biological state of donor tissue influences subsequent recipient immunity and contributes to heterogeneity in allograft outcomes. Donor-resident macrophages, endothelial cells, fibroblasts, extracellular matrix, and tissue-resident lymphocytes constitute an immunologically active myocardial niche that encounters ischemia-reperfusion injury and recipient immune effectors immediately after implantation. Experimental and human studies demonstrate the dynamic coexistence and replacement of donor- and recipient-derived immune populations, with recipient cells acquiring phenotypes within the graft microenvironment. We distinguish transient donor-tissue activation from genuine tissue immune memory, which would require persistence of an exposure-induced molecular or functional state and an altered response to a subsequent challenge. Potential mechanisms include trained innate immunity, epigenetic and metabolic reprogramming, endothelial inflammatory memory, and persistent stromal-immune interactions. We propose that allograft biology be investigated at the level of the donor-recipient immune pair and outline longitudinal single-cell, spatial, and cell-of-origin approaches to test this concept in human heart transplantation.
    Keywords:  cardiac allograft vasculopathy; donor tissue; donor–recipient interaction; heart transplantation; immune memory; macrophages; single-cell analysis; spatial transcriptomics; tissue-resident immunity; trained immunity
    DOI:  https://doi.org/10.3390/ijms27208985
  5. Life Sci. 2026 Oct 24. pii: S0024-3205(26)00558-8. [Epub ahead of print]406 124749
    Immunometabolic checkpoint: The dual regulatory role of macrophages in islet destruction in type 1 diabetes.
    Jin Deng, Jianliang Lu, Wei Wang, Qingyang Liu.
      Macrophage immunometabolic states are important determinants of inflammatory and reparative responses in type 1 diabetes (T1D). Within the diabetic islet, glycolysis, lipid metabolism, mitochondrial function, and metabolite-dependent epigenetic and post-translational mechanisms converge to regulate macrophage signaling, chromatin accessibility, and inflammatory output. M1-like/pro-inflammatory macrophages promote β-cell injury through nitric oxide and cytokine production, whereas M2-like/reparative states support efferocytosis, immune tolerance, and tissue homeostasis. These interconnected pathways form immunometabolic checkpoints that may be therapeutically targeted to reshape the islet immune microenvironment. Precision delivery strategies may further enable cell- and context-specific modulation while limiting systemic effects.
    Keywords:  Epigenetics; Immunometabolism; Inflammation; Macrophages; Metabolic reprogramming; Trained immunity; Type 1 diabetes
    DOI:  https://doi.org/10.1016/j.lfs.2026.124749
  6. iScience. 2026 Nov 20. 29(11): 117816
    Low-frequency parasitized cells in bone marrow alter myelopoiesis following immunization with the live attenuated Leishmania major Cen -/- vaccine.
    Nazli Azodi, Thalia Pacheco-Fernandez, Laura Klenow, Hannah Markle, Nikki Tirrell, Alexander Murray, Meghan Brino, Supriya Kumar, Nirmallya Acharyya, Erica Silberstein, Abhay R Satoskar, Spyros Karaiskos, Hira L Nakhasi, Sreenivas Gannavaram.
      Leishmaniasis lacks an effective vaccine. We developed a live-attenuated Leishmania major Centrin-deficient strain (LmCen -/-) that is safe and protective in murine and canine models through IFN-γ-producing effector T cells. Because persistent low-level infection supports durable immunity, we investigated latent parasites and immune remodeling in the bone marrow. Dual single-cell RNA sequencing detected parasitized bone marrow cells 28 days after intradermal inoculation with either virulent LmWT or attenuated LmCen -/-. Flow cytometry showed increased myelopoiesis following LmCen -/- immunization compared with LmWT infection. Cell-cell communication analysis implicated enhanced granulin-Sort3 signaling as a potential driver of this response. Bone marrow monocytes from LmCen -/--immunized mice efficiently cleared virulent LmWT parasites in co-culture, consistent with the induction of trained innate immunity. These findings identify the bone marrow as an active site of anti-Leishmania immune programming and suggest that LmCen -/- vaccination promotes durable protection through coordinated adaptive and innate mechanisms.
    Keywords:  HSC; bone marrow immunity; leishmania; live attenuated vaccines; persistent infection; scRNA-seq; trained immunity
    DOI:  https://doi.org/10.1016/j.isci.2026.117816
  7. Biochim Biophys Acta Mol Cell Res. 2026 Oct 24. pii: S0167-4889(26)00139-4. [Epub ahead of print]1874(1): 120240
    Platelet-macrophage crosstalk in cardiac inflammation and remodeling.
    Firdos Ahmad, Rizwan Qaisar, Meganathan Kannan, Abdul W Ansari.
      Cardiac injury and chronic heart disease are increasingly recognized as multicellular processes driven by dynamic interactions between immune and thrombotic signaling networks. Although platelets and macrophages have been extensively studied individually, the molecular mechanisms through which their reciprocal interactions regulate cardiac inflammation and remodeling remain incompletely defined. A comprehensive understanding of this cellular crosstalk is needed to define the signaling pathways that couple acute injury responses to chronic maladaptive remodeling. Among these interactions, platelet-macrophage crosstalk has emerged as an important regulator of inflammatory responses and tissue remodeling within the injured myocardium. Beyond their traditional roles in hemostasis and innate immunity, platelets communicate with macrophages through adhesion molecules, soluble mediators, and extracellular vesicles, thereby modulating macrophage activation and functional reprogramming. Platelet-derived mediators, including P-selectin, CD40L, PF4 (CXCL4), CCL5, and platelet-derived extracellular vesicles, modulate macrophage inflammatory signaling, cytokine production, redox balance, metabolic reprogramming, and pro-fibrotic responses relevant to cardiac remodeling. During acute myocardial injury, these interactions facilitate immune-cell recruitment, efferocytosis, and tissue repair, whereas persistent platelet-macrophage communication promotes chronic inflammation, extracellular matrix remodeling, and progression to heart failure. This review summarizes current molecular insights into platelet-macrophage interactions, focusing on receptor-mediated signaling, extracellular vesicle cargo transfer, immunometabolic regulation, and redox-dependent pathways. We also discuss emerging evidence linking this axis to trained immunity and inflammatory memory and highlight potential molecular targets for modulating maladaptive immune remodeling in cardiovascular disease.
    Keywords:  Cardiac; Crosstalk; Macrophage; Platelet; Remodeling; Trained immunity
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120240
  8. Neurochem Res. 2026 Oct 27. pii: 312. [Epub ahead of print]51(6):
    β-Glucan Pretreatment Attenuates Single Prolonged Stress-Associated Behavioural and Neuroinflammatory Changes in Male Mice.
    Jinxin Li, Minxiu Ye, Xu Lu, Qijun Dai, Chao Huang, Jie Peng.
      Post-traumatic stress disorder (PTSD) is a severe psychiatric disease with limited options for prevention. Neuroinflammation is a key factor in PTSD pathogenesis. Innate immune preconditioning, the prior mild stimulation of microglia, can induce tolerance to PTSD. Because β-glucan is a natural polysaccharide found in fungal cell walls that can stimulate microglia, we investigated whether β-glucan preconditioning can prevent PTSD-like behaviors in the single prolonged stress (SPS) male mouse model. A single intraperitoneal injection of β-glucan (10 and 20, but not 5 mg/kg) one day before SPS significantly prevented SPS-induced increases in contextual and cued fear freezing, as well as anxiety-like behaviors in the elevated plus maze and open field tests. β-glucan (20 mg/kg) administered 1 or 5 days before SPS maintained its protective effects, but this effect was lost at a 10-day interval. Notably, a second injection 10 days after the first and 1 day before SPS, or four daily injections ending 10 days before SPS, also prevented SPS-induced fear- and anxiety-like behaviors. After the final behavioral tests at the end of the SPS model recovery period, β-glucan pretreatment was found to prevent SPS-induced upregulation of tumor necrosis factor-α (Tnf-α), interleukin-1β (Il-1β), and Il-6 mRNA in the brain. Additionally, pharmacological inhibition (minocycline) or depletion (PLX3397) of microglia abolished β-glucan's behavioral and neuroinflammatory protection. These findings demonstrate that β-glucan, likely through stimulation of microglia, prevents PTSD-like behaviors and attenuates neuroinflammatory responses. As β-glucan can be obtained naturally, it may be a potential drug for preventing PTSD-like behaviors, at least in animals.
    Keywords:  Innate immune tolerance; Microglia; Neuroinflammation; PTSD; β-glucan
    DOI:  https://doi.org/10.1007/s11064-026-04934-0
  9. Nat Immunol. 2026 Oct 29.
    Autophagy in macrophages curtails IL-1α-mediated immune priming against lung infections.
    Xiaoyan Cui, Xiwen Zhang, Siwei Feng, Junnan Chen, Shengxiao Zhang, Georgia R Sampedro, Hongyan Gao, Irnov Irnov, Qun Lu, Megan T Baldridge, Adrianus C M Boon, Ken Cadwell, Victor J Torres, Juliane Bubeck Wardenburg, Mo Chen, Guanxiang Liang, Herbert W Virgin, Christina L Stallings, Ya-Ting Wang.
      Host resistance to infection is initially determined by how well primed the innate immune system is to respond on first exposure to an invader, yet the mechanisms underlying this priming remain incompletely understood. Here we found that basal autophagy suppressed the expression of Il1a in alveolar macrophages (AMs) and an otherwise protective innate immune priming against Staphylococcus aureus and influenza A virus (IAV), independently of the microbiome and adaptive immunity. Inactivating autophagy genes in AMs led to elevated expression of IL-1α in AMs, which subsequently enhanced IL-1R-MyD88 signaling in neutrophils and increased the recruitment of myeloid cells to the lung. As a result, autophagy-deficient mice showed more efficient clearance of S. aureus along with reduced lung damage and inflammation. Similar to genetic inactivation of autophagy, overexpression of IL-1α in AMs conferred broad spectrum protection against S. aureus and IAV, suggesting a possible strategy to fine-tune immune responses to combat important respiratory infections.
    DOI:  https://doi.org/10.1038/s41590-026-02699-w
  10. Nat Commun. 2026 10 27. pii: 10959. [Epub ahead of print]17(1):
    Inflammatory memory primes the intestine for enhanced regenerative potential.
    Borja Arozamena, Ilias Moraitis, Loris Mularoni, Olga Wienskowska, Jasin Taelman, Milica Stefanovic, Ignasi Modolell Farré, Ferran Guedea, Mònica Díaz, Jordi Guiu.
      How do inflammation and activation of the regenerative genetic program affect intestinal epithelial cell behavior and shape responses to future injuries? Following injury, which typically induces intestinal stem cell (ISC) death, regeneration occurs via the proliferation of surviving ISCs and via cellular plasticity through dedifferentiation of progenitors and committed cells. While inflammation and cellular plasticity are hallmarks of regeneration, its long-term effects on epithelial cell behavior are not well understood. Using single cell multiomics, we demonstrate that inflammatory exposure and cellular plasticity imprint a lasting transcriptional and epigenetic memory on ISCs and their progeny, priming them for enhanced repair after subsequent injuries. Mechanistically, we identify IFN-γ as a critical driver of this primed regenerative state. These findings uncover how prior inflammation reprograms regenerative capacity, with implications for tissue resilience and disease susceptibility.
    DOI:  https://doi.org/10.1038/s41467-026-79014-6
  11. Nature. 2026 Oct 28.
    Diet at disease onset determines tissue inflammatory memory.
    Zewen Jiang, John M Tayeri, Im-Hong Sun, Joy Li, E Dean Merrill, Longhui Qiu, Dongliang Zhang, Vrinda Johri, Megan E Dobson, Ruriko Watanabe, Mazharul Maishan, Margaret M Lowe, Chihiro Tabuchi, Sarah G Gayer, Arum Yoo, Nandini U Borkar, Jiaxi Wang, Han Yin, Shin Shyan Chuah, Preetal Deshpande, Brittany Davidson, Jessica Tsui, Nicholas F Kuhn, Tristan Courau, Sophie Curio, Vinh Q Nguyen, Abdullah El Kurdi, Raymond J Cho, Jeffrey B Cheng, Katrin J Svensson, Michael D Rosenblum, Mark R Looney, Alexis J Combes, Ari B Molofsky, Michael A Matthay, James M Gardner, Sagar P Bapat.
      Obesity, which is often associated with prolonged exposure to an obesogenic diet, substantially alters immunity1-7, but whether brief dietary changes shape acute inflammatory responses and long-term tissue memory remains unclear. Here we show that transient high-fat diet (HFD) exposure at the onset of acute type 17 skin inflammation exacerbates disease in lean mice to levels comparable to those associated with chronic obesity. This effect is restricted to a discrete 4-day peri-initiation window; HFD outside this window has no impact, whereas switching obese mice to a low-fat diet (LFD) during a similar window fully blunts disease amplification. Mechanistically, HFD rapidly recruits neutrophils into the skin, and neutrophils in challenged skin express high levels of Nlrp3 (ref. 8) and Il1b. Neutrophil depletion, genetic Nlrp3 deficiency and pharmacological NLRP3 inhibition each blunt the HFD-induced inflammatory amplification. These findings nominate a neutrophil-NLRP3-IL-1β axis that licences pathogenic IL-1R1+CD4+ T helper type 17 (TH17) cells9,10. After recovery, a chromatin-poised tissue-resident memory T cell population persists. Consequently, mice exposed to HFD at disease onset develop exaggerated inflammation upon recurrence, despite recovery and maintenance on LFD. Transient HFD similarly amplifies lung TH17 inflammation through neutrophil- and IL-1R1-dependent mechanisms. Together, these findings show that dietary state during a narrow temporal window can durably reprogram disease trajectory, suggesting that short-lived physiological states may become embedded in local immune memory11 when they coincide with tissue inflammation.
    DOI:  https://doi.org/10.1038/s41586-026-11181-4
  12. Clin Exp Immunol. 2026 Jan 06. pii: uxag061. [Epub ahead of print]220(1):
    Post-acute infection: before we forget it again.
    Helena Borland Madsen, Claus Desler.
      Long COVID did not invent the post-acute phase of infection; it made it impossible to ignore. Acute infections are still often framed as time-limited events that end in recovery, deterioration or death, but this view fails to capture patients who remain biologically and clinically unwell after the acute infection has passed. The problem extends beyond SARS-CoV-2. Post-acute morbidity has been described after influenza, Epstein-Barr virus infection, Q fever, sepsis, and other infections, yet definitions, coding systems, and clinical pathways remain fragmented. We argue that post-acute infection should not be organized only by the initiating pathogen. Such pathogen-centric labels may be clinically tidy, but they risk producing heterogeneous cohorts, diluted biomarker signals, and disease-specific silos that obscure shared mechanisms of incomplete recovery. Instead, the field needs a second axis: the host-recovery state. Persistent inflammation, immune remodelling, loss of tolerance, antigenic stimulation, endothelial dysfunction, mitochondrial impairment, and tissue injury may represent overlapping immunometabolic failure modes across infections. Defining these states over time could help transform post-acute infection from a residual clinical label into a mechanism-informed framework for research, biomarkers, and care.
    Keywords:  Long COVID; infectious diseases; inflammation; mitochondrial dysfunction; post-acute sequelae
    DOI:  https://doi.org/10.1093/cei/uxag061
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