bims-traimu Biomed News
on Trained immunity
Issue of 2026–04–19
thirteen papers selected by
Yantong Wan, Southern Medical University
  1. Molecular and cellular bases of trained immunity.
  2. Trained immunity induction by vaccines adjuvants.
  3. Tissue Context as a Determinant of Trained Innate Immunity: A Conserved Molecular Toolkit with Divergent Functional Outputs.
  4. Trained immunity in respiratory diseases: Mechanisms of action and intervention strategies.
  5. Clinical evidence on BCG vaccination and COVID-19 infection: A systematic review.
  6. Interferon regulatory factor 5 associated neutrophil reprogramming by trained immunity protects against lethal-dose bacterial sepsis.
  7. Training, memory, and tissue adaptation of NK cells and innate lymphoid cells.
  8. Monophosphoryl lipid A boosts macrophage antimicrobial immunity by metabolically regulating source-specific ROS generation.
  9. Immunological mechanistic action of intravenous BCG-mediated protection against tuberculosis.
  10. Environmental factors that regulate host-helminth interactions.
  11. MMP8 mediates CD115 cleavage-dependent elimination of large peritoneal macrophages in response to microbial exposure.
  12. Mechanical memory primes cells for confined migration.
  13. Glycerol enhances mitochondrial metabolism and inflammatory response in pro-inflammatory macrophages.
  1. Immunity. 2026 Apr 14. pii: S1074-7613(26)00112-3. [Epub ahead of print]59(4): 897-910
    Molecular and cellular bases of trained immunity.
    Sarah J Sun, Raúl Aguirre-Gamboa, Luis B Barreiro.
      Innate immune cells can adopt long-lasting functional states following transient stimulation. This process of trained immunity was initially defined in monocytes but occurs in multiple cellular systems, including tissue-resident macrophages and hematopoietic stem and progenitor cells. Trained immunity is mediated through coordinated epigenetic and metabolic alterations that enhance secondary inflammatory responses. In this review, we highlight shared principles across systems while emphasizing how developmental and tissue contexts shape trained immunity. We propose a unifying framework in which metabolic and epigenetic remodeling initiate trained states, but persisting components, such as transcription factor activity and environmental signals, are required for durable maintenance. Understanding how trained immunity is encoded, preserved, and regulated is essential for harnessing its potential in infection, inflammation, and immunotherapy.
    Keywords:  emergency myelopoiesis; epigenetic remodeling; inflammation; innate immunity; trained immunity; transcription factor circuits
    DOI:  https://doi.org/10.1016/j.immuni.2026.03.001
  2. Curr Opin Virol. 2026 Apr 16. pii: S1879-6257(26)00022-2. [Epub ahead of print]76 101530
    Trained immunity induction by vaccines adjuvants.
    Ghazal Sodaifi, Mihai G Netea.
      Recent studies have revealed that cells of the innate immune system can adapt to previous insults (such as infections) and build a de-facto innate immune memory termed trained immunity. This process enables enhanced responses to homologous or heterologous microbial stimuli and is primarily driven by long-lasting epigenetic remodeling coupled with metabolic reprogramming. Vaccine adjuvants are well recognized for their ability to amplify adaptive immune responses by stimulation of antigen-presenting cells, making them a critical component of modern vaccine design. There is increasing evidence suggesting that certain adjuvants can also induce trained immunity, highlighting their ability to enhance vaccine efficacy beyond classical adaptive immune responses. This emerging concept provides new opportunities for antigen selection and adjuvant development with higher immunogenicity in future vaccines.
    DOI:  https://doi.org/10.1016/j.coviro.2026.101530
  3. J Leukoc Biol. 2026 Apr 09. pii: qiag047. [Epub ahead of print]
    Tissue Context as a Determinant of Trained Innate Immunity: A Conserved Molecular Toolkit with Divergent Functional Outputs.
    Mary A Oliver, Xenia D Davis, Julia K Bohannon.
      Trained innate immunity (TI) challenges the traditional view that adaptive immune cells are solely responsible for establishing immune memory. Instead, innate immune cells can develop a form of memory through persistent epigenetic, metabolic, and antimicrobial modifications, enabling them to respond to secondary challenges in a nonspecific manner. While the molecular mechanisms underlying this trained response have been extensively characterized and are well understood, the intrinsic cellular programs driving trained immunity have not been clearly delineated. Further, the influence of tissue-specific microenvironments remains underexplored. Evidence indicates that the heterogeneity observed in trained immune responses is partly attributable to the functional outcomes shaped by trained immunity within diverse tissue microenvironments, underscoring the complexity and context-dependent nature of this adaptive process. In this review, we explore that TI uses a conserved molecular toolkit whose functional output is dictated by tissue microenvironment. Signals such as oxygen tension, microbiota, local metabolites, cytokine release, and damage-associated molecular patterns can also shape trained innate immunity. The resulting outcomes range from increased antimicrobial defense to maladaptive responses that lead to chronic inflammation and tissue damage. Together, we synthesize findings from hematopoiesis and tissue-resident macrophage biology, emphasizing how immunometabolism and epigenetic mechanisms underpin tissue-specific models of TI. This comprehensive framework resolves contradictions observed across different organs and disease states, positioning tissue instruction as a pivotal determinant of innate immune memory. It demonstrates that trained immunity programs are intricately adapted to tissue niches, with profound implications for infection control, inflammatory diseases, tissue regeneration, and the precise therapeutic targeting of innate immune cells.
    Keywords:  Epigenetics; Immunometabolism; Tissue-resident macrophage; Trained innate immunity
    DOI:  https://doi.org/10.1093/jleuko/qiag047
  4. Chin Med J Pulm Crit Care Med. 2026 Mar;4(1): 39-60
    Trained immunity in respiratory diseases: Mechanisms of action and intervention strategies.
    Szu-Yu Lee, Jing Li, Xikun Zhou.
      Trained immunity refers to a form of nonspecific immunological memory established through epigenetic modifications and metabolic reprogramming in innate immune cells following stimulation. This concept offers a novel framework for understanding and treating respiratory diseases. Chronic inflammation and dysregulated immune memory resulting from respiratory immune imbalance underlie many respiratory conditions, including infectious pneumonia, asthma, and chronic obstructive pulmonary disease (COPD). The core mechanisms of trained immunity involve epigenetic regulation-mediated by histone modifications such as histone H3 lysine 4 trimethylation (H3K4me3)-and metabolic reprogramming, exemplified by glycolysis. Trained immunity exhibits a "double-edged sword" effect in respiratory diseases: appropriate activation enhances pathogen clearance, whereas excessive activation may lead to sustained inflammation and tissue damage. Intervention strategies targeting trained immunity-such as vaccine-induced training, metabolic modulation, and natural product application-have shown clinical promise. However, the field faces challenges, including a lack of specific regulatory approaches and clinically applicable biomarkers. Future efforts should focus on deepening mechanistic insights and facilitating the clinical translation of precise interventions, thereby opening new paradigms for the prevention and treatment of respiratory diseases.
    Keywords:  Asthma; Bronchiectasis; Chronic obstructive pulmonary disease; Infectious respiratory diseases; Inflammation modulation; Innate immune memory; Lung cancer; Pulmonary fibrotic diseases; Trained immunity
    DOI:  https://doi.org/10.1016/j.pccm.2026.02.003
  5. Respir Investig. 2026 Apr 10. pii: S2212-5345(26)00056-0. [Epub ahead of print]64(3): 101422
    Clinical evidence on BCG vaccination and COVID-19 infection: A systematic review.
    Praneta Yadav, Arpita Singh, Manju Kumari, Sunil Kumar Verma, Devendra Singh.
      The COVID-19 pandemic, starting in late 2019, led to the rapid development of SARS-CoV-2 vaccines, though early availability was limited, and variants like Delta and Omicron impacted their effectiveness. The Bacillus Calmette-Guérin (BCG) vaccine, used to prevent tuberculosis, has attracted interest for its potential non-specific protective effects against COVID-19. This review systematically evaluates the role of BCG vaccination in enhancing innate immune responses and its utility against COVID-19, focusing on mechanisms like trained immunity and cross-protection. It also discusses recent studies on BCG's impact on COVID-19 outcomes. Preliminary clinical trial findings suggest potential benefits of BCG vaccination against COVID-19, but the evidence remains inconclusive. Therefore, this review highlights the necessity of additional studies to determine whether BCG can prevent COVID-19 infection, mitigate severe outcomes and hospitalizations, and serve as a preventive tool for future viral pandemics.
    Keywords:  BCG vaccine; COVID-19; Innate immunity; SARS-CoV-2; Trained immunity
    DOI:  https://doi.org/10.1016/j.resinv.2026.101422
  6. Drug Resist Updat. 2026 Apr 05. pii: S1368-7646(26)00044-0. [Epub ahead of print]87 101393
    Interferon regulatory factor 5 associated neutrophil reprogramming by trained immunity protects against lethal-dose bacterial sepsis.
    Liyuan Li, Chibo Liu, Mingming Zhang, Yawei Gou, Xinfang Zhang, Yan Qi, Lingling Liu, Renhao Wang, Jiashan Jiang, Ruonan Wang, Shengnan Wang, Wenbo Shan, Xi Zhao, Haokun Li, Zhenbo Wang, Jing Li, Wei Sun.
      Intra-abdominal infection is a major driver of sepsis with limited therapeutic options. Although innate immune memory (trained immunity) has been studied in monocytes and macrophages, its role in neutrophils is unclear. Here, using mouse and zebrafish models of bacterial peritonitis, we show that a low-dose bacterial exposure induces an interferon regulatory factor 5 (Irf5) + neutrophil state; upon lethal re-challenge, these cells differentiate into Cd274⁺ checkpoint-enriched and Fth1⁺ ROS-adaptive subsets. Functionally, primed-then-challenged mice exhibit amplified early cytokine responses, increased reactive oxygen species and neutrophil extracellular trap formation, and reduced bacterial burden with improved survival compared with lethal controls. Consistent with a cross-species program, Irf5 overexpression in zebrafish similarly enhances resistance to patient-derived pathogens. Mechanistically, Irf5-MyD88 signaling links priming to neutrophil fate diversification and heightened antibacterial function. These findings suggest Irf5-based modulation may inform future strategies to strengthen innate immunity and improve host resistance in infectious disease settings.
    Keywords:  Bacterial infection; Irf5; Neutrophil reprogramming; Sepsis; Trained-immunity-like
    DOI:  https://doi.org/10.1016/j.drup.2026.101393
  7. Immunity. 2026 Apr 14. pii: S1074-7613(26)00124-X. [Epub ahead of print]59(4): 911-927
    Training, memory, and tissue adaptation of NK cells and innate lymphoid cells.
    Georg Gasteiger, Thomas Ossner, Christin Friedrich.
      Innate lymphoid cells (ILCs) and natural killer (NK) cells can acquire durable functional changes following activation. These include features of trained immunity, such as epigenetic reprogramming and poised effector states, and of adaptive immune memory, including clonal-like expansion and acquired tissue residency. Together, these features enable adaptation of NK/ILC populations and their contributions to tissue homeostasis, immune surveillance, and secondary responses. Reciprocally, local niches are reshaped by inflammatory episodes, influencing immune cell behavior beyond resolution. Here, we discuss the layers of memory-like features in innate lymphocytes, highlighting emerging questions of NK/ILC differentiation and reprogramming, as well as their residency, interactions, and functions in tissues. We explore how immune experience modulates these processes, with implications for inflammatory diseases, vaccination, and immunotherapy.
    Keywords:  NK cells; innate lymphoid cells; innate memory; tissue-circuits
    DOI:  https://doi.org/10.1016/j.immuni.2026.03.013
  8. Front Immunol. 2026 ;17 1745195
    Monophosphoryl lipid A boosts macrophage antimicrobial immunity by metabolically regulating source-specific ROS generation.
    Dan Hao, Benjamin D Klein, Margaret A McBride, Julia K Bohannon, Naeem K Patil, Xenia D Davis, Mary A Oliver, Mei Lin Ning Dye, Sara Weidenbach, Jamey D Young, Edward R Sherwood.
       Introduction: Monophosphoryl lipid A (MPLA), a toll-like receptor (TLR) 4 agonist and licensed vaccine adjuvant, reprograms innate immune cells to confer protection against diverse pathogens. However, the metabolic and molecular adaptations supporting this response remain poorly defined.
    Methods: The contributions of discrete reactive oxygen species (ROS) sources-including NADPH oxidase 2 (NOX2), xanthine oxidase (XO), mitochondria, and inducible nitric oxide synthase (iNOS)-to MPLA-induced macrophage antimicrobial activity were examined using genetic deletion or pharmacologic inhibition. Metabolic and redox adaptations supporting this response were assessed by analyzing oxidative pentose phosphate pathway (oxPPP) activity, glutathione-dependent antioxidant systems, and mitochondrial oxidative phosphorylation in MPLA-primed macrophages.
    Results: MPLA enhanced macrophage clearance of Pseudomonas aeruginosa by coordinating source-specific ROS generation. NOX2 was essential for this response, as its pharmacologic inhibition or genetic deletion markedly diminished MPLA-induced microbicidal responses. MPLA also induced XO, providing auxiliary ROS that acted additively with NOX2-derived ROS to support bacterial clearance. MPLA activated the oxPPP to generate NADPH, which was essential for supporting phagocytosis and maintaining glutathione-dependent redox homeostasis. Additionally, MPLA promoted mitochondrial oxidative phosphorylation to sustain phagocytic capacity. Mitochondrial ROS (mROS) were tightly constrained by induction of antioxidant systems, including superoxide dismutase 2 (SOD2), heme oxygenase-1 (HO-1) and glutathione, and were dispensable for antimicrobial protection. iNOS-derived nitric oxide did not contribute to the MPLA-induced antimicrobial phenotype.
    Conclusion: These findings define the metabolic and redox circuits driving MPLA-induced antimicrobial immunity and establish its potential as a host-directed antimicrobial therapy beyond vaccine adjuvancy.
    Keywords:  NADPH; NADPH oxidase (NOX); innate immune memory; monophosphoryl lipid A (MPLA); reactive oxygen species (ROS); trained immunity; xanthine oxidase (XO)
    DOI:  https://doi.org/10.3389/fimmu.2026.1745195
  9. Cell Mol Life Sci. 2026 Apr 16.
    Immunological mechanistic action of intravenous BCG-mediated protection against tuberculosis.
    Sangwon Choi, Jiyun Park, Jung Joo Hong, Sung Jae Shin, Ju Mi Lee.
      
    Keywords:  Antibody responses; Intravenous BCG; TRM ; Trained immunity; Tuberculosis; iBALT
    DOI:  https://doi.org/10.1007/s00018-026-06173-6
  10. Trends Parasitol. 2026 Apr 13. pii: S1471-4922(26)00051-6. [Epub ahead of print]
    Environmental factors that regulate host-helminth interactions.
    Eric Y Helm, Tighe Christopher, Alejandra Lopez Espinoza, Natalie Santillano, Elia D Tait Wojno.
      Soil-transmitted helminths (STHs) infect over a billion people worldwide. Individual outcomes vary, ranging from subclinical, mild infections to recurrent or severe disease. Emerging evidence reveals that susceptibility to STH infection reflects a multilayered integration of past and present environmental factors. At mucosal surfaces, STHs activate type 2 immune, epithelial, and neuronal circuits, while microbial- and diet-derived signals promote homeostasis. Environmental signals tune the transcriptional programs that control these events, shaping interleukin-13-driven effector functions required for worm expulsion. Concurrently, infection and inflammation history imprint immune and epithelial compartments, leading to durable epigenetic remodeling and altering responsiveness to STHs upon reexposure. Understanding how environmental factors impact host-helminth interactions offers new opportunities to predict susceptibility and design interventions that enhance anti-helminth immunity.
    Keywords:  anemia; neuronal–immune axis; soil-transmitted helminth; trained immunity; type 2 immunity
    DOI:  https://doi.org/10.1016/j.pt.2026.03.003
  11. Cell Rep. 2026 Apr 09. pii: S2211-1247(26)00312-8. [Epub ahead of print]45(4): 117234
    MMP8 mediates CD115 cleavage-dependent elimination of large peritoneal macrophages in response to microbial exposure.
    Shilpi Giri, Andrew T Martin, Alexandra Safronova, Sophia I Eliseeva, Sara Ahmed, Samantha F Kwok, Felix Yarovinsky.
      Macrophages, critical for tissue homeostasis and immune regulation, undergo significant changes during microbial infections. Certain inflammatory conditions can trigger the loss of these macrophages through a process called macrophage disappearance reaction (MDR), which, in turn, affects the ongoing immune response. Here, we show that the presence of bacteria in the peritoneal cavity, which can be mimicked by Toll-like receptor (TLR) stimulation, leads to loss of cell surface CD115, also known as macrophage colony-stimulating factor receptor (M-CSFR). This loss renders macrophages unresponsive to M-CSF signaling and induces their disappearance. MMP8, an enzyme released by macrophages in response to LPS, was responsible for CD115 cleavage and its subsequent loss from the cell surface during MDR, establishing a biochemical mechanism for this phenomenon. Our findings extended to human cells, highlighting the role of MMP8 in CD115 shedding. This study enhances our understanding of MDR initiation and proposes a regulatory mechanism for inflammatory responses by restricting essential growth factors.
    Keywords:  CD115; CP: immunology; LPS; M-CSF; M-CSFR; MMP8; macrophage; macrophage disappearance reaction; tissue-resident macrophages
    DOI:  https://doi.org/10.1016/j.celrep.2026.117234
  12. Cell Rep. 2026 Apr 16. pii: S2211-1247(26)00345-1. [Epub ahead of print]45(4): 117267
    Mechanical memory primes cells for confined migration.
    Jia Wen Nicole Lee, Yeji Chang, Malhar S Chitnis, Yixuan Li, Xu Gao, Avery Rui Sun, Jin Zhu, Jennifer L Young, Andrew W Holle.
      When migratory cells move between stiffness niches in vivo, they encounter confined spaces imposed by extracellular matrix (ECM) networks. Cells from one niche possess mechanosensitive adaptations that influence their response to new environments, a concept known as mechanical memory. How this memory is acquired and how it influences migratory potential in confinement remain poorly understood. Here, we combine stiffness priming using polyacrylamide hydrogels with a confinement platform to screen memory across healthy and transformed cells. Using a dose-and-passage approach, we find that cells primed on soft substrates navigate confinement more efficiently. Bulk RNA sequencing identifies NFATC2 as a transcription factor mediating mechanical memory through genetic reprogramming. Inhibition of NFATC2 confirms that it is required for memory acquisition and enhanced confined migration. Highly invasive cancer cells fail to retain mechanically induced phenotypes following cue removal, suggesting differential adaptation strategies. These findings establish mechanical memory as a cell-intrinsic regulator of confined migration.
    Keywords:  CP: cell biology; NFATC2; cell migration; confined migration; mechanical memory; mechanotransduction; substrate stiffness; transcriptional regulation
    DOI:  https://doi.org/10.1016/j.celrep.2026.117267
  13. EMBO Rep. 2026 Apr 14.
    Glycerol enhances mitochondrial metabolism and inflammatory response in pro-inflammatory macrophages.
    Manami Tanaka, Takako Hishiki, Tomomi Matsuura, Masato Yasui, Shunsuke Chikuma, Mariko Hara-Chikuma.
      Although glycerol is a ubiquitous metabolite in mammalian systems, its cellular metabolic pathways and functions have not been fully elucidated. Here, we find that elevated extracellular glycerol modulates intracellular metabolism and pro-inflammatory responses of macrophages. In pro-inflammatory macrophages stimulated with lipopolysaccharide, glycerol is taken up through glycerol channels including Aquaporin 3 (AQP3) and metabolized to glycerol-3-phosphate (G3P), which is then converted to dihydroxyacetone phosphate by glycerol-3-phosphate dehydrogenase 2 (GPD2). This glycerol-driven pathway enhances mitochondrial ATP production, potentially by supplying electrons to the electron transport chain (ETC) via GPD2, and by upregulating the transcription of genes encoding ETC complexes.　In addition, glycerol supplementation elevates intracellular acetyl-CoA levels, promotes histone acetylation at the promoters of pro-inflammatory cytokine genes, and consequently increases cytokine gene expression, suggesting enhanced pro-inflammatory response. In vivo experiments, macrophage-specific AQP3 conditional knockout mice exhibit reduced weight gain and adipose tissue inflammation in a high-fat diet-induced obesity model. Our findings provide novel insights into the metabolic regulation and macrophage inflammation by extracellular glycerol.
    Keywords:  Glycerol; Inflammation; Macrophage; Metabolism; Obesity
    DOI:  https://doi.org/10.1038/s44319-026-00747-y
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