bims-traimu 2026-01-25 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–01–25
ten papers selected by
Yantong Wan, Southern Medical University

Trained Immunity in Interorgan Communication and Vascular Inflammation.
Western lifestyle linked to maladaptive trained immunity.
Active LXR signaling, coupled with elevated mitochondrial and glycolytic metabolism contributes to GM-CSF-induced trained immunity.
Engineered Akkermansia muciniphila vesicles for targeted pyroptosis and trained immunity to enhance immunotherapy in hepatocellular carcinoma.
Trained Tolerance and Cardioprotection: Different Triggers, Same Outcome.
Exposure to immune stimuli reprograms alveolar macrophages to acquire neutrophil-derived antimicrobial molecules to prevent staphylococcal pneumonia.
Upregulation of m6A writer WTAP by histone lactylation promotes inflammatory response via TLR2 in neutrophils.
[β-Glucan reprograms neutrophils to promote disease tolerance against influenza A virus].
Single-cell landscape of immune cells in multiple autoimmune diseases.
GPR81 Activation by Lactate Delays Inflammation Resolution in Acute Lung Injury.

Arterioscler Thromb Vasc Biol. 2026 Jan 22.

Trained Immunity in Interorgan Communication and Vascular Inflammation.

Arthur Liesz.

  Despite major advances in acute reperfusion therapies, patients surviving ischemic stroke or myocardial infarction remain at high risk for long-term cardiovascular and metabolic comorbidities. Emerging evidence identifies trained immunity, the long-lasting reprogramming of innate immune progenitors, as a central driver of this interorgan communication. Sterile insults such as stroke or myocardial infarction imprint persistent inflammatory memory via long-lasting reprogramming of bone marrow hematopoietic progenitors, biasing myelopoiesis and generating proinflammatory monocytes that target distant organs. This central trained immunity explains how a single ischemic event can precipitate cardiac dysfunction, accelerate atherosclerosis, or exacerbate metabolic disease, thereby contributing to multimorbidity in vascular patients. Understanding these systemic immune circuits provides a conceptual framework for developing interventions that interrupt maladaptive inflammatory memory. Finally, we discuss emerging therapeutic strategies to prevent maladaptive innate immune memory and mitigate chronic vascular inflammation and multimorbidity.

Keywords:  acetylation; cardiovascular diseases; histones; ischemic stroke; monocytes

DOI:  https://doi.org/10.1161/ATVBAHA.125.323130
Elife. 2026 Jan 21. pii: e105835. [Epub ahead of print]15

Western lifestyle linked to maladaptive trained immunity.

Aurelia Josephine Merbecks, Christabel Mennicken, Dennis Marinus de Graaf, Kateryna Shkarina, Theresa Wagner, Eicke Latz.

  Trained immunity (TI) refers to a state of innate immune cells that, after encountering an initial stimulus and undergoing epigenetic reprogramming and metabolic changes, allows them to respond more effectively to a subsequent challenge. TI yields a survival advantage, particularly in a pathogen-rich context. However, maladaptive TI may damage the host by exacerbating inflammatory diseases. Here we review which aspects of Western lifestyle may contribute to maladaptive TI, including a Western diet, periodontitis, chronic psychological stress, and environmental triggers such as air pollution and microplastics. Finally, we consider lifestyle intervention as a way to prevent or reduce the impact of maladaptive TI.

Keywords:  Western diet; autoinflammation; immunology; infectious disease; inflammation; interleukin-1; maladaptive; trained immunity

DOI:  https://doi.org/10.7554/eLife.105835
Front Immunol. 2025 ;16 1685796

Active LXR signaling, coupled with elevated mitochondrial and glycolytic metabolism contributes to GM-CSF-induced trained immunity.

Yuanyuan Liu, Arslan Hamid, Hannah Hardege, Qian Zhang, Helena Körner, Merle Leffers, Noelia A Gonzalez, Gerhard Liebisch, Marcus Hoering, Hannes Findeisen, Katarzyna Placek, Mihai G Netea, Holger Reinecke, Dennis Schwarz, Yahya Sohrabi.

  Granulocyte-macrophage colony-stimulating factor (GM-CSF) contributes to the host defense and the pathogenesis of inflammatory diseases at least in part through inducing trained immunity (TI), however, the mechanism remains poorly characterized. In this paper, we systematically investigated the associated metabolic and epigenetic reprogramming, with a particular focus on the role of liver X receptors (LXRs) in this process. We employed a comprehensive experimental approach, including in vitro isolation and purification of human monocytes from healthy donors, cytokine assays, quantitative PCR, Seahorse metabolic analysis, flow cytometry, and chromatin immunoprecipitation (ChIP), shotgun lipidomics, as well as transcriptomic data analysis to investigate GM-CSF-induced trained immunity. Our results demonstrate that GM-CSF induces TI by enhancing cellular metabolism, as evidenced by increased glycolysis, mitochondrial activity, fatty acid oxidation, and pyruvate metabolism. Lipidomics and RNA sequencing analyses revealed upregulation of lipid synthesis, high triglyceride storage, and acetyl-CoA-producing pathways, leading to increased histone acetylation in GM-CSF-trained cells. Furthermore, glycolysis and mitochondrial metabolism are essential for establishing TI in these cells. Notably, pharmacological inhibition of GM-CSF activated LXR signaling, which potentially mediated via PPARγ, attenuated GM-CSF-induced TI via reducing glycolytic flux and histone acetylation while activation of LXR amplified these effects. Together, these results highlight the role of LXR in linking cellular metabolism with epigenetic reprogramming and demonstrate that elevated metabolic activity and active LXR signaling both are essential for GM-CSF-induced trained immunity. Importantly, these pathways may represent therapeutic targets for modulating GM-CSF-driven maladaptive inflammation in chronic inflammatory diseases.

Keywords:  GM-CSF; acetyl-CoA; glycolysis; histone modification; mitochondrial metabolism; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2025.1685796
Cell Rep Med. 2026 Jan 20. pii: S2666-3791(25)00597-X. [Epub ahead of print]7(1): 102524

Engineered Akkermansia muciniphila vesicles for targeted pyroptosis and trained immunity to enhance immunotherapy in hepatocellular carcinoma.

Lanxiang Huang, Yuan Rong, Minghui Guo, Min Liu, Fei Long, Wei Zhong, Yue Hu, Xin He, Jiurong He, Diwei Zheng, Chunhui Yuan, Fubing Wang.

  Hepatocellular carcinoma (HCC) features a tumor immunosuppressive microenvironment (TIME) and limited response to immune checkpoint inhibitors (ICIs). To address this, we develop ultrasound-responsive nanoparticles by encapsulating PD-L1-targeting small interfering RNA (siRNA) and sonodynamic metal-organic frameworks (MOFs) into bacterial membrane vesicles (BMVs) derived from Akkermansia muciniphila. The siRNA-MOF@BMV (SMB) demonstrates HCC-specific accumulation via N-acetylgalactosamine (GalNAc) and induces pyroptosis through NLRP3/Caspase-1/GSDMD pathway activation under ultrasound, releasing tumor antigens. Simultaneously, SMB further induces trained immunity in tumor-associated macrophages (TAMs), promoting CXCL9+ phenotypes that enhance antigen presentation and chemotaxis capacity. This increases cytotoxic CD8+ T cell infiltration and reduces exhausted T cells, reshaping the TIME. Furthermore, SMB exhibits superior tumor suppression compared to clinical ICIs through systematic evaluations in orthotopic HCC mouse models, primary HCC models, patient-derived xenograft (PDX), and organoid models. SMB presents a multifunctional immunotherapeutic strategy integrating targeted pyroptosis induction, innate immune training, and ICI delivery, representing a potent immunotherapeutic agent for HCC.

Keywords:  bacterial membrane vesicles; immune checkpoint inhibitors; metal-organic frameworks; pyroptosis; trained immunity; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.xcrm.2025.102524
Am J Physiol Heart Circ Physiol. 2026 Jan 20.

Trained Tolerance and Cardioprotection: Different Triggers, Same Outcome.

Xiaofeng Yang, Abdelkarim Sabri.



Keywords:  Cardioprotection; beta-adrenergic receptors; immune tolerance; inflammation; lipopolysaccharide

DOI:  https://doi.org/10.1152/ajpheart.00983.2025
bioRxiv. 2025 Dec 05. pii: 2025.12.03.692039. [Epub ahead of print]

Exposure to immune stimuli reprograms alveolar macrophages to acquire neutrophil-derived antimicrobial molecules to prevent staphylococcal pneumonia.

Amit Sharma, Linda M Heffernan, Venkatesh Mayandi, Seetharama D Jois, William N Beavers, Basel H Abuaita.

The protective adaptation of innate immune defenses against respiratory pathogens has been linked to previous exposure to immune stimuli; however, the underlying mechanisms of these adaptations are not yet fully understood. Here, we show that pre-exposure to a low dose of non-specific immune stimuli or infection protects against subsequent lethal methicillin-resistant Staphylococcus aureus (MRSA) challenge. This enhanced protection concurs with increased alveolar macrophages (AMs) resulting from a self-renewal process in the lungs. Importantly, these AMs are programmed to acquire neutrophil-released antimicrobial enzymes from the extracellular space to kill MRSA, prevent tissue damage, and rapidly restore lung homeostasis. The gain of AM functions is dependent on differential gene expression, including expression of the efferocytosis receptor MerTK and the anti-apoptotic regulator Bcl-xL. Thus, our data highlight that the acquisition of neutrophil enzymes by AMs is an integral component of innate immune adaptation.

DOI: https://doi.org/10.64898/2025.12.03.692039
Sci China Life Sci. 2026 Jan 14.

Upregulation of m6A writer WTAP by histone lactylation promotes inflammatory response via TLR2 in neutrophils.

Bailu Du, Wenting Song, Yiming Zhang, Yan Yin, Yuanjie Zhou, Yi Pan, Ruwen Yang, Muxiu Jiang, Nan Shen, Qihua Fu, Jianye Zang, Yue Tao, Xi Mo.

  Elevated lactate levels are a hallmark of severe infections and are associated with poor outcomes in sepsis patients, but the underlying mechanisms remain poorly understood. Recent findings have shown that lactate can covalently modify histones (e.g., histone lactylation) in macrophages, acting as a critical epigenetic regulator of inflammatory response. Here, we demonstrate that histone lactylation also occurs in neutrophils-the first immune cells mobilized during acute inflammation-and is functionally important for their activation. Using both DMSO-differentiated HL-60 (dHL-60) cells and primary neutrophils, we found that LPS stimulation significantly increased intracellular lactate levels and histone lactylation, particularly at the H4K8 site. These changes enhanced cytokine release, ROS production, and chemotaxis. Lactate further amplified these effects, while inhibition of glycolysis or p300 suppressed them. Multi-omics analyses revealed substantial enrichment of H4K8la at the promoter region of WTAP, a key m6A methyltransferase component, promoting its expression via CEBP/β recruitment. WTAP knockdown significantly reduced m6A modifications of TLR2 mRNA and impaired its stability. Both WTAP knockdown and TLR2 inhibition markedly dampened the inflammatory responses. Importantly, this glycolysis-H4K8la-WTAP-TLR2 axis was further validated in LPS-induced septic mice and pediatric sepsis patients, highlighting its clinical relevance. In summary, our findings uncover a novel lactate-driven epigenetic-post-transcriptional regulatory circuit that amplifies neutrophil inflammatory responses, expanding the regulatory framework of innate immunity and providing potential therapeutic targets for hyperinflammation.

Keywords:  TLR2; WTAP; histone lactylation; inflammation; m6A; neutrophils; sepsis

DOI:  https://doi.org/10.1007/s11427-024-3081-9
Med Sci (Paris). 2026 Jan;42(1): 104

[β-Glucan reprograms neutrophils to promote disease tolerance against influenza A virus].

Solène Ozil, Éva Todorovska, Samuel Terki, Maria Del Mar Naranjo-Gomez.

DOI: https://doi.org/10.1051/medsci/2025202
iScience. 2026 Jan 16. 29(1): 114515

Single-cell landscape of immune cells in multiple autoimmune diseases.

Lin Zhu, Wujianan Sun, Kun Chen, Zitian Liu, Meifang Tang, Chen Jiang, Yu Shi, Qian Liu, Wen Zhang, Junyu Wang, Ao Zheng, Jun Lin, Guosheng Wang, Xiaomei Li, Xu Liu, Kun Qu.

  Autoimmune pathologies arise from dysregulated immune activation, yet conserved molecular programs across autoimmune contexts remain incompletely characterized. Here, we analyzed integrative single-cell RNA sequencing data of over 1.3 million cells from 239 samples spanning six autoimmune diseases, revealing disease-specific and cell type-specific transcriptional programs. Systematic immune profiling identified 41 functionally annotated gene clusters (GCs) with cross-disease activation. We identified a cytotoxic CD8 + T cell-enriched gene cluster (GC40) that drives enhanced cytotoxic function and clonal expansion across four autoimmune diseases. In parallel, we identified a secretory granule lumen-associated GC08 that is highly expressed in CD14 + monocytes and promotes plasma cell activation through upregulation of TNFSF13B secretion. Furthermore, we leveraged a disease classifier to discriminate autoimmune disease types and healthy states. Our study provides both a resource and a predictive framework at the single-cell level, supporting future targeted therapies for autoimmune diseases.

Keywords:  Bioinformatics; Genomics; Immunology

DOI:  https://doi.org/10.1016/j.isci.2025.114515
FASEB J. 2026 Jan 31. 40(2): e71423

GPR81 Activation by Lactate Delays Inflammation Resolution in Acute Lung Injury.

Zhongjie Liang, Chengxi Shen, Junyan Zeng, Xingling Wei, Jinling Wei, Yuan Cao, Shengwei Jin, Qian Wang.

  Acute respiratory distress syndrome (ARDS) involves impaired macrophage function in clearing apoptotic cells. The link between clinical hyperlactatemia in ARDS patients and poor outcomes prompted this study on the immunometabolic role of lactate in disease progression. In an LPS-induced ARDS mouse model, mice received either exogenous lactate or a lactate dehydrogenase inhibitor. Inflammatory cell infiltration was evaluated through flow cytometry and histological analysis with hematoxylin and eosin staining. Lactate signaling was confirmed in GPR81-deficient mice. In vitro, lactate metabolism during efferocytosis was studied using primary Alveolar Macrophages (AMs). Lactate accumulation, neutrophil infiltration, and elevated inflammatory factors were observed in this ARDS model. External lactate delayed inflammation resolution and worsened lung injury. GPR81-/- mice exhibited reduced neutrophil infiltration and better outcomes. Macrophages produced substantial amounts of lactate during efferocytosis in vitro, concurrent with upregulated expression of the glucose transporter Glut1, the lactate transporter MCT1, and the lactate receptor GPR81. Pharmacological inhibition using an LDH inhibitor, an MCT1 antagonist, or extra lactate significantly impaired efferocytic capacity. Efferocytosis triggered Myc upregulation in vitro, which was suppressed by exogenous lactate. Genetic ablation of GPR81 elevated both MCT1 and Myc expression. Silencing Myc via siRNA significantly impaired efferocytosis in vitro. These findings indicate that the activation of GPR81 by lactate delays the resolution of inflammation in acute lung injury. This effect may be attributed to the suppression of alveolar macrophage efferocytosis, which subsequently impairs the clearance of apoptotic cells and exacerbates lung injury.

Keywords:  ARDS; Efferocytosis; GPR81; Macrophages; lactate

DOI:  https://doi.org/10.1096/fj.202501547RR