bims-traimu Biomed News
on Trained immunity
Issue of 2025–10–19
eight papers selected by
Yantong Wan, Southern Medical University
  1. Trained immunity: induction of an inflammatory memory in disease.
  2. Memory in Misfire: The Gut Microbiome-Trained Immunity Circuit in Inflammatory Bowel Diseases.
  3. Cytokine-induced memory-like responses in endothelial cells link chronic inflammation to vascular disease risk.
  4. 2-Deoxy-D-glucose reshapes the sepsis-trained stressed granulocytes by comprehensive alterations of the transcriptional landscape.
  5. Monophosphoryl Lipid A induces tolerance against single prolonged stress-induced PTSD-like behavior and neuroinflammatory responses in mice.
  6. Lung tissue-resident memory T cells optimize protection by IL-10 regulation of innate immunity.
  7. IL-1 family cytokines in inflammation and immunity.
  8. Toward a comprehensive map of Rab-mediated cargo transport to migrasomes.
  1. Cell Res. 2025 Oct 14.
    Trained immunity: induction of an inflammatory memory in disease.
    Titus Schlüter, Yuri van Elsas, Bram Priem, Athanasios Ziogas, Mihai G Netea.
      The innate immune system adapts its behavior based on previous insults, mounting an enhanced response upon re-exposure. Hematopoietic progenitors in the bone marrow and peripheral innate immune cells can undergo epigenetic and metabolic reprogramming, establishing an innate immune memory known as trained immunity. The concept of trained immunity recently gained relevance in our understanding of how innate immunity is regulated in various diseases. This review explores the role of trained immunity in infections, autoimmune disease, cardiovascular disease, cancer, and neurodegenerative disease. We discuss how trained immunity can provide heterologous protection against infections, as it has been induced for decades by the Bacillus Calmette Guérin vaccine, how it can help counteract immunosuppression, and how it can be inappropriately induced leading to chronic inflammation. By understanding how trained immunity is involved in processes leading to health and disease, novel therapeutic strategies can be developed.
    DOI:  https://doi.org/10.1038/s41422-025-01171-y
  2. Int J Mol Sci. 2025 Oct 03. pii: 9663. [Epub ahead of print]26(19):
    Memory in Misfire: The Gut Microbiome-Trained Immunity Circuit in Inflammatory Bowel Diseases.
    Binbin Yang, Jiacheng Wu, Xiaohua Hou, Tao Bai, Shi Liu.
      Inflammatory bowel disease (IBD) demonstrates chronic relapsing inflammation extending beyond adaptive immunity dysfunction. "Trained immunity"-the reprogramming of innate immune memory in myeloid cells and hematopoietic progenitors-maintains intestinal inflammation; however, the mechanism by which gut microbiome orchestration determines protective versus pathological outcomes remains unclear. Microbial metabolites demonstrate context-dependent dual effects along the gut-bone marrow axis. Short-chain fatty acids typically induce tolerogenic immune memory, whereas metabolites like succinate and polyamines exhibit dual roles: promoting inflammation in certain contexts while enhancing barrier integrity in others, influenced by cell-specific receptors and microenvironmental factors. Interventions include precision probiotics and postbiotics delivering specific metabolites, fecal microbiota transplantation addressing dysbiotic trained immunity, targeted metabolite supplementation, and pharmacologic reprogramming of pathological myeloid training states. Patient stratification based on microbiome composition and host genetics enhances therapeutic precision. Future research requires integration of non-coding RNAs regulating trained immunity, microbiome-immune-neuronal axis interactions, and host genetic variants modulating microbiome-immunity crosstalk. Priorities include developing companion diagnostics, establishing regulatory frameworks for microbiome therapeutics, and defining mechanistic switches for personalized interventions.
    Keywords:  gut microbiome; inflammatory bowel diseases; innate immune memory; trained immunity
    DOI:  https://doi.org/10.3390/ijms26199663
  3. Mol Omics. 2025 Oct 14.
    Cytokine-induced memory-like responses in endothelial cells link chronic inflammation to vascular disease risk.
    Kieu T T Le, Nick Keur, Heleen Middelkamp, Thuy Linh Do, Albert van den Berg, Valeria Orlova, Leo A B Joosten, Mihai G Netea, Cisca Wijmenga, Iris Jonkers, Sebo Withoff, Andries D Van der Meer, Vinod Kumar.
      Chronic inflammation plays a central role in the progression of both infectious and vascular diseases, yet its impact on endothelial cells (ECs), which form the interface between blood and tissue, remains poorly understood. Given their constant exposure to inflammatory cytokines such as TNF-α and IFN-γ, we set out to investigate how cytokine induced inflammation shapes EC function at the molecular level. Using primary human umbilical vein endothelial cells (HUVECs), we modeled repeated cytokine exposure to simulate a chronically inflamed microenvironment. Transcriptomic and epigenetic profiling revealed that ECs respond to this chronic stimulation with durable transcriptional and chromatin changes. These responses included phenotypes resembling immune cell priming, training, and tolerance, which are commonly associated with innate immune memory, a phenomenon whereby innate immune cells mount altered responses following previous stimulation. Although we did not observe classical trained immunity pathways, several genes known to mediate immune training, including TLR2, IL1B, and HDAC9, exhibited enhanced activation following TNF-α re-exposure. IFN-γ stimulation uniquely induced sustained expression and chromatin accessibility at MHC class II loci, suggesting cytokine-specific modes of reprogramming. Functionally, re-stimulated ECs exhibited enhanced monocyte adhesion in a 3D vessel-on-chip model, highlighting the relevance of these molecular changes to vascular inflammation. Moreover, the regulatory regions altered by cytokine exposure were enriched for disease-associated SNPs, particularly those linked to COVID-19, sepsis, and cardiovascular disorders. In summary, these findings reveal that repeated exposure to cytokines as seen in chronic inflammation can induce memory-like responses in ECs and suggest that endothelial reprogramming may contribute to vascular dysfunction.
    DOI:  https://doi.org/10.1039/d5mo00136f
  4. Gene. 2025 Oct 13. pii: S0378-1119(25)00617-1. [Epub ahead of print]972 149828
    2-Deoxy-D-glucose reshapes the sepsis-trained stressed granulocytes by comprehensive alterations of the transcriptional landscape.
    Fangyuan Li, Xiaoqiang Liu, Zhen Yu, Can Zhang, Shuai Tong, Liyuan Liu, Ju Zhang, Hongxia Zhu, Hui Zeng, Nan Ding.
      The secondary infections following sepsis pose a significant clinical challenge due to hyperinflammatory organ injury, which is primarily driven by maladaptive trained immunity (TRIM) in stressed granulocytes. Glucose metabolic reprogramming serves as a crucial mechanism underlying TRIM and is increasingly acknowledged as a promising therapeutic target for preventing cytokine storms following reinfections. Here, we employed recovery mice subsequent to the cecal ligation and puncture (CLP) procedures to model reinfection following sepsis and confirm the beneficial effects of 2-Deoxy-D-glucose (2-DG), which inhibits boosted glucose metabolism in stressed granulocytes. The 2-DG treatment leads to a marked reduction in TNF-α secretion, reactive oxygen species (ROS) production, and neutrophil extracellular traps (NETs) formation upon secondary stimulation while alleviating pulmonary inflammation in vivo. We conducted RNA sequencing to investigate how 2-DG treatment reshapes the transcriptomic profile of stressed granulocytes. Our findings revealed the effective reversion of LPS-induced pro-inflammatory responses after sepsis training, including cell migration, chemotaxis, and immune cell recruitment. However, 2-DG also caused extensive and non-specific suppressions of granulocyte biofunctions, such as cell-to-cell signaling and nucleic acid metabolism, indicating potential unexpected consequences. Furthermore, analysis of the upstream regulators in the 2DG-associated gene network identified CD44 as a promising alternative therapeutic target to 2-DG. This study provides novel insights into the pharmacological mechanism network associated with 2-DG treatment and supports the implementation of immunosuppressive strategies via targeted remodeling of glycose metabolism. This approach may serve as an effective therapeutic intervention for addressing secondary infections in sepsis.
    Keywords:  2-deoxy-D-glucose treatment; Secondary infection; Sepsis; Stressed granulocyte; Trained immunity
    DOI:  https://doi.org/10.1016/j.gene.2025.149828
  5. Eur J Pharmacol. 2025 Oct 14. pii: S0014-2999(25)01010-6. [Epub ahead of print] 178256
    Monophosphoryl Lipid A induces tolerance against single prolonged stress-induced PTSD-like behavior and neuroinflammatory responses in mice.
    Fu Li, Minxiu Ye, Wenbin Xia, Lijuan Tong, Rongrong Song, Rongrong Yang, Wenfeng Hu, Lijun Liu, Chao Huang, Xu Lu, Zhuo Chen.
      Neuroinflammation is a pathological process that favors the development of post-traumatic stress disorder (PTSD). Our previous studies have reported that pre-stimulation of microglia by low-dose lipopolysaccharide (LPS) before stress stimulation prevents PTSD by blocking neuroinflammation. Since monophosphoryl lipid A (MPL) is a derivative of LPS that lacks the undesirable properties of LPS but still has immune-enhancing effects, we investigated its effect on PTSD-like behaviors induced by single prolonged stress (SPS). The results showed that a single injection of MPL at a dose of 400, 800 or 1600, but not 200 μg/kg one day before stress stimulation prevented SPS-induced fear- and anxiety-like behaviors. A single injection of MPL (800 μg/kg) either 1 day or 5 days but not 10 days before stress stimulation resulted in tolerance to SPS-induced fear- and anxiety-like behaviors. In addition, a second MPL injection 10 days after the first injection or a 4× MPL injection 10 days before stress stimulation prevented SPS-induced fear- and anxiety-like behaviors. These effects of MPL were associated with decreases in tumor necrosis factor-α (Tnf-α), interleukin-1β (Il-1β), Il-6, and ionized calcium-binding adaptor molecule 1 (Iba-1) mRNA in the brains of SPS mice. Inhibition or depletion of microglia abolished the preventive effect of MPL on PTSD-like behavior and neuroinflammatory responses. These results suggest that MPL prevents the occurrence of PTSD-like behaviors by blocking the progression of neuroinflammation in the brain. Due to its low toxicity, MPL could be developed as a drug to prevent the onset of PTSD, at least in animals.
    Keywords:  PTSD; microglia; monophosphoryl lipid A; neuroinflammation; prevention
    DOI:  https://doi.org/10.1016/j.ejphar.2025.178256
  6. J Exp Med. 2026 Jan 05. pii: e20242307. [Epub ahead of print]223(1):
    Lung tissue-resident memory T cells optimize protection by IL-10 regulation of innate immunity.
    Alexander Y Yang, Julia Davis-Porada, Daniel H Paik, Alex B George, Brea H Brown, Paige L Ruschke, Peter A Sims, Ziv Frankenstein, Anjali Saqi, Donna L Farber.
      Respiratory viral infections establish tissue-resident memory T cells (TRM) in the lung, which provide optimal protection against subsequent infections, though the underlying mechanisms are incompletely understood. Here, we demonstrate in a mouse model of heterosubtypic influenza infection that lung TRM attenuate inflammation by macrophages during secondary versus primary responses, in part, through production of the immunoregulatory cytokine IL-10. During secondary infections, lung TRM were the predominant producers of early IL-10; inhibiting early IL-10 signaling resulted in increased macrophage-mediated inflammation, morbidity, and lung pathology. Moreover, lung TRM were shown to directly modulate lung macrophage responses and polarization in depletion experiments. Finally, IL-10 enhanced IFN-γ production by lung memory CD8+ T cells. Human influenza-specific TRM isolated from lungs recapitulated robust IL-10 expression associated with augmented effector responses of murine TRM. These data support a dual role of TRM in coordinating in situ secondary responses-augmenting effector responses for robust viral clearance while dampening inflammation to limit tissue damage.
    DOI:  https://doi.org/10.1084/jem.20242307
  7. Cell Mol Immunol. 2025 Oct 14.
    IL-1 family cytokines in inflammation and immunity.
    Cecilia Garlanda, Irene Di Ceglie, Sebastien Jaillon.
      Interleukin-1 (IL-1) was the first interleukin identified as a potent proinflammatory and multifunctional molecule involved in innate immune responses against microbes, as well as in conditions of tissue injury associated with infections and sterile conditions. IL-1 is part of a large system, the IL-1 system, comprising a family of ligands that act as agonists, receptor antagonists, and anti-inflammatory cytokines, as well as a family of receptors that includes signaling receptor complexes, decoy receptors and negative regulators. All the members of the IL-1 system are involved in inflammatory diseases, innate and adaptive immune responses, conditions associated with dysmetabolism, and cancer by affecting both the tumor microenvironment and cancer cells. The deregulated or excessive activation of several pathways associated with the IL-1 system may lead to detrimental inflammatory or immune reactions, including autoinflammatory, autoimmune, infectious and degenerative diseases. The negative regulation of the IL-1 system mediated by antagonists, decoy receptors, scavengers, and dominant-negative molecules plays nonredundant roles in controlling these conditions. Owing to the central role of IL-1 in the pathogenesis of inflammation-driven diseases, IL-1 blocking agents are approved for clinical use in several inflammatory conditions, and inhibitory agents for other members of the family are under development. Here, the complexity of the IL-1 system, the involvement of its different members in inflammation-driven diseases, and the therapeutic approaches to target members of pathways associated with these conditions are presented and discussed.
    Keywords:  Immunopathology; Lymphoid cells; inflammation; innate immunity; myeloid cells
    DOI:  https://doi.org/10.1038/s41423-025-01358-8
  8. Sci China Life Sci. 2025 Oct 10.
    Toward a comprehensive map of Rab-mediated cargo transport to migrasomes.
    Yiling Wen, Yong Li, Jiayi Chen, Dianxing Liu, Yuanchao Li, Ying Li, Haohao Tang, Peizhen Gao, Wenmin Tian, Ning Shen, Yang Chen.
      
    DOI:  https://doi.org/10.1007/s11427-025-3073-2
This page is being maintained by Thomas Krichel. It was last updated on 2025‒10‒19 at 3:36.