bims-traimu Biomed News
on Trained immunity
Issue of 2025–10–26
nine papers selected by
Yantong Wan, Southern Medical University
  1. Resident memory macrophages and trained innate immunity at barrier tissues.
  2. Rewiring the bone marrow: Evolution and the transcriptional architecture of trained immunity.
  3. Erythropoietin prolongs graft survival in mice by counteracting trained immunity.
  4. Exploring Functionally Enhanced BLP-Trained Macrophage Subpopulations in S. Aureus Infection: Underlying Mechanisms and Therapeutic Significance.
  5. A non-canonical immunometabolic function of BRD3 during sepsis.
  6. Dual effects and balanced regulation of cytokines in sepsis.
  7. A crucial role of the malate aspartate shuttle in metabolic reprogramming in TNF-induced SIRS.
  8. Protective Role for Itaconate During Inhaled Allergen Challenge.
  9. Clarifying National Institutes of Health Investment Estimates for Sepsis Research.
  1. Elife. 2025 Oct 20. pii: e106549. [Epub ahead of print]14
    Resident memory macrophages and trained innate immunity at barrier tissues.
    Alisha Kang, Michael D'Agostino, Sam Afkhami, Mangalakumari Jeyanathan, Zhou Xing.
      Innate immune memory, or trained innate immunity (TII), represents a form of immunological adaptation in which innate immune cells, including myeloid and lymphoid cells, retain a trained state following prior exposure to immunological stimuli. This long-lasting modification either enhances or reduces the innate immune response to subsequent heterologous infections or inflammatory insults. While TII often provides protective benefits, including enhanced protection against pathogens and tumors, it can contribute to maladaptive inflammation in certain conditions. Epigenetic changes and metabolic reprogramming are key drivers of innate immune memory, but it is important to distinguish between transient acute changes and persistent modifications that define bona fide innate immune memory. Innate immune memory can be induced centrally, through systemic events that train hematopoietic progenitors in the bone marrow, or locally, via tissue-resident cells such as macrophages. The presence of trained tissue-resident immune cells offers significant advantages, but their responses may not always result in universally enhanced protection. This review explores recent advances in the understanding of tissue-resident memory macrophages and TII at barrier tissue sites, including the lung, skin, gut, and peritoneum, highlighting the implications for vaccine and immunotherapeutic strategies. Ongoing research promises to accelerate progress in this field and inform new clinical and vaccinology approaches.
    Keywords:  barrier tissues; immunology; inflammation; lung; memory macrophages; trained immunity; vaccine
    DOI:  https://doi.org/10.7554/eLife.106549
  2. Elife. 2025 Oct 24. pii: e107551. [Epub ahead of print]14
    Rewiring the bone marrow: Evolution and the transcriptional architecture of trained immunity.
    Sarah J Sun, Raúl Aguirre-Gamboa, Luis B Barreiro.
      The epigenetic adaptation of innate immune cells to inflammatory stimuli, or trained immunity, represents an evolutionarily conserved feature of host defense. Recent advances have revealed that such adaptations can occur at the level of hematopoietic stem and progenitor cells, resulting in long-lasting epigenetic reprogramming of the immune system. However, a comprehensive mechanistic understanding of these processes remains incomplete, limiting our capacity to predict or therapeutically manipulate the adaptive capacity of hematopoiesis. In this review, we survey the current literature to support a model of hematopoietic memory whose stimulus-specific nuances are shaped by specific cytokine environments and driven by the combinatorial activity of key transcription factors. Comparative analyses underscore the evolutionary conservation and essential biological roles of these factors, suggesting that trained immunity may reflect the strategic repurposing of ancient transcriptional programs for the purpose of enhancing host defense.
    Keywords:  epigenetics; genetics; genomics; trained immunity; transcription factors
    DOI:  https://doi.org/10.7554/eLife.107551
  3. Am J Transplant. 2025 Oct 22. pii: S1600-6135(25)03060-6. [Epub ahead of print]
    Erythropoietin prolongs graft survival in mice by counteracting trained immunity.
    Sofia Bin, Barbara Franchin, Irene Ramos, Marina Iskhakova, Johan Noble, Chiara Cantarelli, Nina Goerlich, Leonardo V Riella, Jamil Azzi, Jordi Ochando, Paolo Molinari, Gaetano La Manna, Paolo Cravedi.
      Upon activation, macrophages undergo epigenetic and metabolic reprogramming, resulting in stronger responses to subsequent insults (trained immunity), and, in the case of transplant, in accelerated rejection. Erythropoietin (EPO), a kidney-produced erythropoietic hormone, exerts immune-modulatory effects through the ligation of EPO receptor (EPOR) expressed on myeloid cells, but its effects on trained immunity are unknown. C57BL/6 mice receiving BALB/c cardiac allografts and treated with CpG (a toll-like receptor agonist that activates myeloid cells) exhibited accelerated rejection, whereas treatment with EPO - either at the time of CpG injection or afterward - restored prolonged graft survival induced by anti-CD40L monoclonal antibody therapy. Mechanistically, EPO suppressed alloreactive T cell proliferation, enhanced regulatory T cell populations, and reversed CpG-induced inflammatory cytokine production and epigenetic changes in murine macrophages. These effects were absent in mice with myeloid cell-specific deletion of EPOR, underscoring the critical role of EPOR signaling in EPO's protective mechanism. Key results were replicated in human cells. This study demonstrates that EPO counteracts trained immunity in macrophages, promoting immune tolerance and prolonging allograft survival, providing potential therapeutic insights for transplant immunology.
    Keywords:  innate immunity; macrophage; monocyte; trained immunity; transplant
    DOI:  https://doi.org/10.1016/j.ajt.2025.10.013
  4. Adv Sci (Weinh). 2025 Oct 21. e17142
    Exploring Functionally Enhanced BLP-Trained Macrophage Subpopulations in S. Aureus Infection: Underlying Mechanisms and Therapeutic Significance.
    Yantong Wan, Yinghao Hong, Xiangjun Ji, Jing Xiang, Jinxi Liu, Lixin Liang, Meng Ren, Wenhan Chen, Tengfei Xu, Zhijie Li, Tieliu Shi, Yong Jiang, Huaping Liang, Jinghua Liu.
      Tolerance to bacterial lipoprotein (BLP) is an evolved protective mechanism characterized by an enhanced resistance of BLP-trained macrophages to microbial infection. However, the underlying mechanisms are not fully understood, and their potential for translational clinical application needs further evaluation. In the present study, through single-cell RNA sequencing (scRNA-seq), transcriptomic profiles in both naïve and BLP-trained bone marrow-derived macrophages (BMDMs) during Staphylococcus aureus infection are analyzed, and 13 distinct BMDM subpopulations are identified. Notably, BLP-trained tolerance initiates the emergence of two novel BMDM subpopulations, C5 and C7, characterized by increased antibacterial gene expression and enhanced anti-inflammatory and antioxidative stress abilities. Moreover, BLP-trained BMDMs demonstrate activation of the NRF2 signaling pathway, thereby augmenting an antioxidative stress response and mitigating oxidative stress-induced cell damage and ferroptosis, while undergoing metabolic reprogramming characterized by enhanced glycolysis and oxidative phosphorylation pathways, together with increased anti-inflammatory metabolites. Critically, in vivo adoptive transfer of BLP-trained BMDMs protects mice against sepsis-associated lethality by attenuating systemic inflammatory response, accelerating bacterial clearance, and alleviating organ damage. Collectively, the present study presents a single-cell atlas of murine BMDMs at rest and under S. aureus infection following BLP training, which reveals novel mechanisms of BLP training-altered macrophage immunity and identifies macrophage subpopulations responsible for an enhanced resistance to infection, thus offering new preventive and therapeutic strategies for sepsis.
    Keywords:  BLP; NRF2; antioxidative stress; macrophage; single‐cell transcriptomics; trained immunity
    DOI:  https://doi.org/10.1002/advs.202417142
  5. Dev Cell. 2025 Oct 20. pii: S1534-5807(25)00601-X. [Epub ahead of print]
    A non-canonical immunometabolic function of BRD3 during sepsis.
    Nian Wang, Jiao Liu, Runliu Wu, Feng Chen, Chunhua Yu, Herbert Zeh, Xianzhong Xiao, Haichao Wang, Timothy R Billiar, Ling Zeng, Jianxin Jiang, Daolin Tang, Rui Kang.
      Sepsis is a life-threatening condition characterized by a dysregulated host innate immune response to pathogen infection. Here, we identify a pathological role for bromodomain-containing 3 (BRD3) in driving septic shock by upregulating aconitate decarboxylase 1 (ACOD1) in monocytes and macrophages via a non-canonical pathway. Mechanistically, lipopolysaccharide triggers an interaction between BRD3 and tripartite motif containing 21 (TRIM21), which activates CREB binding lysine acetyltransferase (CREBBP) via its E3 ligase activity, facilitating CREBBP's binding to and acetylation of cyclic adenosine monophophate (cAMP)-response-element-binding protein 1 (CREB1). BRD3 then recognizes and phosphorylates acetylated CREB1 at the transcription-activating site, thereby upregulating ACOD1 transcription. In four murine models of infection, myeloid-specific Brd3 deletion (Brd3Mye-/-) or pharmacological intervention using small-molecule inhibitor OTX015 confers significant protection, reducing systemic inflammation and organ injury, similar to the effects observed in Acod1Mye-/- mice. In patients with sepsis, elevated BRD3 levels correlate with accelerated inflammation, increased disease severity, and a greater risk of in-hospital death. These findings establish BRD3 as a potential therapeutic target for managing infection-associated immune dysregulation.
    Keywords:  ACOD1; BRD3; immunometabolism; inflammation; itaconate; sepsis
    DOI:  https://doi.org/10.1016/j.devcel.2025.09.016
  6. Trends Immunol. 2025 Oct 21. pii: S1471-4906(25)00246-7. [Epub ahead of print]
    Dual effects and balanced regulation of cytokines in sepsis.
    Changli Wang, Chenglong Zhu, Xiaoming Deng, Wangzheqi Zhang.
      Sepsis, a life-threatening condition triggered by infection, disrupts the body's immune balance and remains a major global health challenge. This forum explores the dual roles of cytokines in sepsis: their overactivation drives 'cytokine storms,' and dysregulation leads to immunosuppression. It also discusses regulatory mechanisms for developing targeted therapies.
    DOI:  https://doi.org/10.1016/j.it.2025.10.002
  7. Front Immunol. 2025 ;16 1652516
    A crucial role of the malate aspartate shuttle in metabolic reprogramming in TNF-induced SIRS.
    Louise Nuyttens, Marah Heyerick, Maxime Roes, Elise Moens, Céline Van Dender, Charlotte Wallaeys, Tino Hochepied, Steven Timmermans, Jolien Vandewalle, Claude Libert.
      Tumor necrosis factor (TNF) causes a lethal systemic inflammatory response syndrome (SIRS) which is characterized by significant metabolic alterations. Based on liver RNA sequencing, we found that TNF impairs the malate-aspartate shuttle (MAS), an essential redox shuttle that transfers reducing equivalents across the inner mitochondrial membrane thereby recycling cytosolic NAD+. This downregulation of MAS genes in TNF-induced SIRS likely results from loss of HNF4α function, which appears to be the key transcription factor involved. Using Slc25a13-/- mice lacking citrin - a crucial MAS component - we demonstrate that MAS dysfunction exacerbates TNF-induced metabolic dysregulations and lethality. Disruptive NAD+ regeneration leads to diminished mitochondrial β-oxidation, leading to elevated levels of circulating free fatty acids (FFAs) and to hepatic lipid accumulation. Simultaneously, MAS dysfunction promotes glycolysis coupled to lactate production and reduces lactate-mediated gluconeogenesis, culminating in severe hyperlactatemia that triggers VEGF-induced vascular leakage. Overall, MAS dysfunction contributes to metabolic failure and lethality in TNF-induced SIRS, highlighting its potential as a promising, therapeutic target.
    Keywords:  TNF-induced SIRS; carbohydrate metabolism; citrin; lipid metabolism; malate aspartate shuttle
    DOI:  https://doi.org/10.3389/fimmu.2025.1652516
  8. Allergy. 2025 Oct 24.
    Protective Role for Itaconate During Inhaled Allergen Challenge.
    Gesa J Albers, Patricia P Ogger, Christina Michalaki, Helen Stölting, Simone A Walker, Anna Caldwell, John M Halket, Kathryn Duvall, Atia Batool, Lisha Joshi, Helen O'Brien, Cormac McCarthy, Timothy Hinks, Gail M Gauvreau, Paul M O'Byrne, Clare M Lloyd, Adam J Byrne.
       BACKGROUND: Asthma is a chronic, heterogeneous disease characterised by airway remodelling, inflammation, and mucus production. Airway macrophages' functions are underpinned by changes in cellular metabolism. The TCA cycle-derived metabolite itaconic acid (whose synthesis is mediated by aconitate decarboxylase) is a master regulator of macrophage function; however, its role during inhaled allergen challenge is not clear. The objective of this study was to define the role of itaconate during inhaled allergen challenge.
    METHODS: Sputum metabolite levels were measured in participants with mild allergic asthma undergoing allergen inhalation challenge, and in a second cohort, baseline levels in mild, moderate, and severe asthmatics. Airway inflammation, lung function, and bronchoalveolar lavage metabolite levels were assessed in wild-type and aconitate decarboxylase-deficient mice, or in mice treated with inhaled itaconate.
    RESULTS: Allergen inhalation in mild asthmatics led to a significant reduction in sputum itaconate. We found no difference in baseline sputum itaconate levels when comparing healthy controls to mild, moderate, or severe asthmatics. Continuous exposure to aeroallergen in wild type and aconitate decarboxylase-deficient mice showed no change in disease phenotype after 48 h, 1, 3, or 5 weeks of allergen exposure. Treatment of house dust mite-exposed mice with inhaled itaconate reduced airway inflammation.
    CONCLUSION: Levels of itaconate are altered after allergen challenge in mild asthmatics and in murine models of disease. Itaconate deficiency did not alter house dust mite-induced pathology at any of the timepoints tested; however, inhaled itaconate ameliorated inflammatory responses to inhaled allergen.
    Keywords:  airway inflammation; allergen exposure; asthma; itaconate; macrophage metabolism
    DOI:  https://doi.org/10.1111/all.70107
  9. Ann Emerg Med. 2025 Nov;pii: S0196-0644(25)00372-5. [Epub ahead of print]86(5): 559-560
    Clarifying National Institutes of Health Investment Estimates for Sepsis Research.
    Ryan A Coute, Patrick J Siler, Michael C Kurz.
      
    DOI:  https://doi.org/10.1016/j.annemergmed.2025.05.027
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