bims-traimu 2026-04-05 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–04–05
ten papers selected by
Yantong Wan, Southern Medical University

Interactions between Innate Immune Memory and the Central Nervous System.
Trained immunity in cancer and autoimmunity: a double-edged sword in immune memory reprogramming.
Trained immunity responses across infectious diseases and cancer vaccines.
Bone marrow rewired: Trained immunity and clonal hematopoiesis in metabolic disease.
Intestinal Stem Cells from Patients with Inflammatory Bowel Disease Retain an Epigenetic Memory of Inflammation.
4-octyl itaconate inhibits cytokine-mediated inflammation via alkylation of TYK2 and JAK1.
Leveraging intraperitoneal delivery of Toll-like receptor agonists to treat peritoneal metastases.
Lactic acid drives NLRP3 inflammasome activation and caspase-1-like cytokine cleavage via intracellular acidification.
Prolonged Wnt3a exposure tolerizes macrophages to inflammatory stimuli.
An In-Silico Study on the Design of Biological Controllers for Sepsis Regulation.

Neuroimmunomodulation. 2026 Mar 30. 1-34

Interactions between Innate Immune Memory and the Central Nervous System.

Rafaela Rodrigues Valerio, Andressa Bernardi, Adriana Bonomo, Rudimar Luiz Frozza.

BACKGROUND: Traditionally, immunology has assumed the dogma that immunological memory is exclusive to cells of the adaptive immune system. However, over the past decade, this paradigm has been challenged by compelling evidence showing that innate immune cells can mount adaptive characteristics, leading to long-term changes in their function. After exposure to infections or sterile inflammation, innate immune cells can exhibit either an enhanced or suppressed inflammatory response upon secondary challenge. This de facto immune memory has been termed trained immunity or immune tolerance, respectively.
SUMMARY: This review outlines both classical and newly described features of innate immune cells, highlighting the concepts of trained immunity and innate tolerance, along with their underlying molecular mechanisms. We also discuss the implications of innate immune memory in microglia and explore the potential therapeutic approaches for manipulating innate immunity in the context of neurodegenerative disorders.
KEY MESSAGES: While trained immunity plays a crucial role in protecting the host against infections, its dysregulation can lead to chronic inflammation, autoimmune diseases, and potentially contribute to the development of neurodegenerative disorders. On the other hand, tolerance can reduce the inflammatory response and promote tissue regeneration but can also result in increased susceptibility to secondary infections. The long lifespan of microglia, coupled with their ability to learn and adapt their response to previously encountered pathogens or stimuli, underscores the potential long-term implications of their innate immune memory for the development of neuropathology.

DOI: https://doi.org/10.1159/000551784
Front Immunol. 2026 ;17 1782830

Trained immunity in cancer and autoimmunity: a double-edged sword in immune memory reprogramming.

Nasrin Salari, Mehrshad Shams, Fatemeh Tavassoli Razavi, Esmaeil Yazdanpanah, Valentyn Oksenych, Dariush Haghmorad.

  Trained immunity, characterized by the long-term functional reprogramming of innate immune cells through epigenetic and metabolic modifications, has emerged as a pivotal concept bridging innate and adaptive immune responses. This review explores the dual role of trained immunity as both a protective mechanism in cancer and a pathogenic driver in autoimmune diseases. We first discuss the underlying mechanisms involving histone modifications, chromatin remodeling, and metabolic pathways such as glycolysis and the mTOR/HIF-1α axis, alongside key regulators including NOD2 and pattern recognition receptors. The contribution of trained immunity to antitumor responses is highlighted through its ability to enhance innate cell cytotoxicity, remodel the tumor microenvironment, and synergize with immune checkpoint blockade and BCG immunotherapy. Conversely, we examine how infections, dysbiosis, and dietary factors can induce maladaptive trained immunity, leading to persistent hyperinflammatory states and exacerbation of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis. Furthermore, we address therapeutic strategies to modulate trained immunity, including small molecules, β-glucan, statins, and BCG derivatives, emphasizing their potential applications in cancer immunotherapy and autoimmunity control. We also underscore the risks of unintended immune activation, such as autoimmune flare-ups during cancer treatment or compromised host defense during immunosuppression. Finally, we discuss future directions, including the development of trained immunity-based vaccines, personalized immunomodulatory approaches, and the integration of multi-omics and artificial intelligence to design patient-specific interventions. Understanding the complex interplay between trained immunity, cancer, and autoimmunity will be crucial for translating these insights into innovative therapeutic strategies.

Keywords:  autoimmune diseases; cancer immunotherapy; epigenetic reprogramming; innate immune memory; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2026.1782830
Trends Immunol. 2026 Apr 02. pii: S1471-4906(26)00066-9. [Epub ahead of print]

Trained immunity responses across infectious diseases and cancer vaccines.

Kaiyu Fu, Rui Zhang, Yusi Wang, Rutie Yin, Li Yang.

  Trained immunity (TRIM), a paradigm-shifting concept in immunology, refers to the long-term functional reprogramming of innate immune cells, enabling enhanced responsiveness to secondary challenges through metabolic and epigenetic remodeling. This phenomenon bridges the gap between innate and adaptive immunity, offering novel strategies for vaccine design that transcend traditional antigen-specific approaches. By exploiting the 'memorylike' properties of monocytes, macrophages, dendritic cells, neutrophils, and natural killer cells, next-generation vaccines aim to achieve broad-spectrum protection, prolonged durability, and heterologous immunity against pathogens and cancers. This review synthesizes recent advances in TRIM research in vaccines, focusing on its mechanisms, translational applications, and future directions in vaccinology.

Keywords:  adjuvant innovation; heterologous protection; innate immune memory; metabolic remodeling; next-generation vaccines

DOI:  https://doi.org/10.1016/j.it.2026.03.005
Metabolism. 2026 Apr 01. pii: S0026-0495(26)00113-7. [Epub ahead of print] 156603

Bone marrow rewired: Trained immunity and clonal hematopoiesis in metabolic disease.

Julia Chronopoulos, George Hajishengallis, Triantafyllos Chavakis.

  Diseases associated with obesity and metabolic dysregulation, such as diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD) promote chronic low-grade inflammation, which in turn, may enhance the risk for cardiovascular disease. Emerging evidence in recent years suggests that chronicity of inflammation involves alterations in bone marrow homeostasis. Obesity-related inflammation and metabolic stress, including hyperglycemia or hyperlipidemia, may trigger rewiring of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow, driving production of myeloid cells with heightened inflammatory capacity that in turn fuel and sustain chronic inflammation. This process is akin to trained immunity and may promote an inflammatory memory that links metabolic disorders to their cardiovascular complications. Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by aging-related emergence of somatic mutations in hematopoietic cells that clonally expand and bear higher inflammatory potential. Importantly, a bidirectional link between CHIP and metabolic disorders as well as their cardiovascular sequelae emerges. Here, we review current concepts regarding the links between bone marrow biology and metabolic diseases and associated chronic inflammation.

Keywords:  Bone marrow; Clonal hematopoiesis; Diabetes; MASLD; Obesity; Trained immunity

DOI:  https://doi.org/10.1016/j.metabol.2026.156603
Cell Mol Gastroenterol Hepatol. 2026 Mar 26. pii: S2352-345X(26)00052-4. [Epub ahead of print] 101774

Intestinal Stem Cells from Patients with Inflammatory Bowel Disease Retain an Epigenetic Memory of Inflammation.

Feda H Hamdan, Mona Farhadipour, Isaiah Perez, Kimberlee Kossick, Hannah Smith, Adam Edwinson, Jose M de Hoyos-Vega, Michelle Gonzalez, David Chiang, Emily Klatt, Kristy Rumer, Mauricio Perez Pachon, Mary Sagstetter, Jessica Friton, Erin Kammer, Alana English, Lucas C S Chini, Jarl F Carnahan, Noah A Baca, Jessie Hohenstein, Rohini Mopuri, Aditya Bhagwate, Laura E Raffals, Rondell Graham, Zhifu Sun, Madhusudan Grover, Alexander Revzin, Michael Kattah, William A Faubion, Brooke R Druliner.

  Intestinal epithelial damage and impaired repair are hallmarks of ulcerative colitis (UC), even after inflammation resolves. Intestinal stem cells (ISCs) can retain stable epigenetic changes after inflammation, highlighting the potential for long-lived epithelial memory in the gut. Inflammatory injury in barrier tissues induces epigenetic memory in epithelial stem cells, and the tendency of UC to relapse at previously inflamed sites led us to hypothesize that ISCs from IBD patients acquire lasting memory of prior inflammation. To test this, we derived colonic organoids from inflamed (I) and noninflamed regions of the same UC patients and propagated in long-term culture. Chromatin profiling revealed 2,252 accessible regions unique to I organoids, associated with stress response, repair, and inflammatory genes. Although these regions remained accessible, ∼95% of associated genes were not upregulated in I organoids, indicating a primed state. Upon inflammatory or injury re-challenge, I organoids exhibited heightened transcriptional responses and accelerated wound closure, despite reduced clonogenicity and impaired barrier function, indicating a retained inflammatory memory program. Our findings demonstrate that human ISCs retain a chromatin-based memory of inflammation that persists in the absence of immune cues and shapes future responses to injury. While this may support epithelial adaptation to secondary insults, it may predispose tissue to relapse in patients with UC.

Keywords:  chromatin accessibility; inflammatory bowel disease; intestinal stem cells; organoids

DOI:  https://doi.org/10.1016/j.jcmgh.2026.101774
Cell Rep. 2026 Mar 30. pii: S2211-1247(26)00257-3. [Epub ahead of print]45(4): 117179

4-octyl itaconate inhibits cytokine-mediated inflammation via alkylation of TYK2 and JAK1.

Weizhen Li, Qiong Zhang, Songqi Jing, Liting Deng, Haiyang Jiang, Jinpeng Zhang, Zhiwu Hong, Zherui Zhang, Shuai Hao, Lei Wu, Tao Zheng, Yilong Yu, Xiao Ma, Xuefeng Wang, Qingchuan Li, Zhentao Yu, Mingda Liu, Jiaxin Yang, Bin Liu, Haiqing Liu, Chujun Ni, Cunxia Wu, Zitian Hu, Pengfei Zheng, Peige Wang, Yun Zhao, Jianan Ren, Xiuwen Wu.

  Itaconate is a Krebs cycle-derived metabolite whose production is catalyzed by immune response gene 1 (IRG1). As an anti-inflammatory metabolite, itaconate primarily exerts its effects through alkylation of target proteins. Previous studies have identified the JAK-STAT pathway as a key therapeutic target in sepsis. Interestingly, we report that itaconate, a metabolite significantly upregulated during metabolic reprogramming, suppresses type I interferon (IFN-I) signaling. Exogenous supplementation with the itaconate derivative 4-octyl itaconate (4OI) inhibits the JAK-STAT pathway. Mechanistically, 4OI inhibits the binding of tyrosine kinase 2 (TYK2) to IFNAR1 and JAK1 to IFNAR2 by alkylating cysteine 192 in TYK2 and cysteine 189 in JAK1. Our research has identified the crucial role of itaconate produced by the tricarboxylic acid (TCA) cycle in restricting JAK-STAT signal transduction, thereby linking metabolism and innate immunity, and provides a theoretical basis for the therapeutic application of 4OI in sepsis.

Keywords:  4-octyl itaconate; CP: immunology; CP: metabolism; IFN-I; IRG1; JAK1; TYK2; inflammation; itaconate; sepsis

DOI:  https://doi.org/10.1016/j.celrep.2026.117179
Expert Opin Drug Deliv. 2026 Apr 04. 1-20

Leveraging intraperitoneal delivery of Toll-like receptor agonists to treat peritoneal metastases.

Huan Yan, Daryl Chia, Sam Ernst, Jesse Demuytere, Sarah Cosyns, Wim Ceelen.

   INTRODUCTION: Peritoneal metastases (PM) remain a major clinical challenge, marked by poor prognosis and a profoundly immunosuppressive tumor microenvironment. Toll-like receptor (TLR) agonists are particularly attractive due to their ability to activate both innate and adaptive immunity, effectively converting 'cold' tumors. However, systemic administration of TLR agonists is hampered by rapid clearance and dose-limiting toxicity. Intraperitoneal (IP) delivery of TLR provides a pharmacokinetic and immunologic advantage in PM treatment by achieving sustained local drug concentrations in the peritoneal cavity while reducing systemic exposure.
AREAS COVERED: We outline the expression, relevant signaling pathways, and immune effects of TLRs. The effects of IP delivery of TLR4, TLR9, and TLR 7/8 agonists observed in vitro and in preclinical models are systematically reviewed, including delivery as nanoparticles or as a prolonged delivery system. The available clinical studies are reviewed, and challenges and future directions are discussed. A systematic literature search across major databases until January 2026 supports these findings.
EXPERT OPINION: Preclinical models and early clinical trials have demonstrated that intraperitoneal administration of TLR agonists can modulate the peritoneal immune microenvironment, reverse local immunosuppression, and synergize with other therapies. Together, the evidence supports IP TLR agonist therapy as a novel and promising strategy for the treatment of peritoneal metastases.

Keywords:  Controlled drug release; Toll-like receptor agonists; immunotherapy; intraperitoneal drug delivery; peritoneal metastases

DOI:  https://doi.org/10.1080/17425247.2026.2655874
Cell Death Dis. 2026 Apr 03.

Lactic acid drives NLRP3 inflammasome activation and caspase-1-like cytokine cleavage via intracellular acidification.

Hsin-An Lin, Hsin-Chung Lin, Ming-Hang Tsai, Yu-Jen Chen, Bo-Ying Bao, Kuen-Jou Tsai, Chieh-Tien Shih, Jau-Song Yu, Kun-Yi Chien, Kuo-Yang Huang, David M Ojcius, Lih-Chyang Chen.

Glycolysis is critical for NLRP3 inflammasome activation, yet the link between lactic acid metabolism and inflammasome signaling remains unclear. Here, we show that stimulation of macrophages with the NLRP3 activators nigericin or ATP induces lactic acid production and efflux via a lactate dehydrogenase-dependent pathway. Accumulation of intracellular lactic acid leads to cytoplasmic acidification, which promotes NLRP3 inflammasome activation. Concurrently, elevated extracellular lactic acid impairs lactate efflux, exacerbating intracellular acidification and amplifying ASC speck formation, caspase-1 activation, and IL-1β secretion. Alkalinization of the extracellular milieu prevents intracellular acidification and abolishes inflammasome activation. Mechanistically, intracellular lactic acidification promoted mitochondrial dysfunction and reactive oxygen species production, and concurrently induced phosphorylation of the stress kinase PKR, which facilitated PKR-NLRP3 interaction and inflammasome assembly through parallel pathways. Independently of inflammasome signaling, lactic acid also directly cleaves pro-IL-1β and pro-IL-18 into mature forms through a mechanism requiring its carboxyl group and mimicking caspase-1 substrate specificity. Mass spectrometry analysis revealed lactic acid-mediated cleavage of pro-IL-1β at Asp116, the canonical caspase-1 site. In a murine model of polymicrobial sepsis induced by cecal ligation and puncture, systemic lactate administration exacerbated inflammation, increased IL-1β levels and neutrophil infiltration, induced hypothermia, and worsened survival. Together, these findings identify intracellular lactic acidification as a metabolic signal that promotes inflammation predominantly through NLRP3 inflammasome activation, while also revealing a potential inflammasome-independent cytokine processing mechanism under conditions of severe metabolic stress.

DOI: https://doi.org/10.1038/s41419-026-08708-y
Front Immunol. 2026 ;17 1752131

Prolonged Wnt3a exposure tolerizes macrophages to inflammatory stimuli.

Megan L Tigue, Rincon Jagarlamudi, Channing Chi, Diana Diaz, Hua-Chang Chen, Quanhu Sheng, Sheau-Chiann Chen, Anna Schwarzkopf, Jeremy A Goettel, Heather H Pua, Ethan Lee, Vivian L Weiss.

   Introduction: Macrophages are highly plastic innate immune cells that have a broad range of phenotypic and functional roles in the body. The Wnt/β-catenin signaling pathway is known to play important roles in regulating the immune system, but the literature contains contradictory evidence for how Wnt impacts macrophages. Given the plasticity of macrophages, as well as the growing interest in utilizing Wnt inhibitors therapeutically, there is a need to better understand how Wnt signaling affects macrophage phenotype and function.
Methods: We treated murine bone marrow derived macrophages with Wnt3a, LPS/IFN-γ, or IL-4 and measured gene/protein expression with bulk RNA sequencing, RT-qPCR, flow cytometry, and immunofluorescence to assess macrophage phenotype.
Results: RNA sequencing of macrophages treated continually for 5 days with Wnt3a demonstrated upregulation in genes associated with chemotaxis, cytokine activity, and both pro- and anti-inflammatory phenotypes. A time-course of Wnt3a treatment revealed acute upregulation of the inflammatory cytokines Il6, Tnf, and Il12b. Later timepoints showed upregulation of regulatory markers, such as Il10. Finally, re-treating with classic inflammatory cytokines revealed a Wnt-induced tolerant phenotype.
Discussion: In this study, we expanded upon past work to show that acute stimulation by Wnt3a induces inflammatory activation of macrophages in a time-dependent manner. Chronic stimulation with Wnt3a, as may be expected in a Wnt-ligand rich tissue microenvironment, caused macrophages to become tolerant to additional inflammatory stimuli and to upregulate markers of an anti-inflammatory phenotype. This study highlights the importance of considering time-dependent plasticity and regulatory feedback mechanisms in understanding macrophage phenotypes.

Keywords:  Wnt signaling; Wnt3a; macrophages; plasticity; regulation; tolerance

DOI:  https://doi.org/10.3389/fimmu.2026.1752131
ACS Omega. 2026 Mar 24. 11(11): 17758-17768

An In-Silico Study on the Design of Biological Controllers for Sepsis Regulation.

Derrick Dankwa, Syeda Simra Shoaib, Leopold N Green, Xun Tang.

Macrophages are versatile innate immune cells that can dynamically shift between proinflammatory (M1) and anti-inflammatory (M2) states to balance immune defense and tissue repair, in response to local microenvironment cues. In sepsis, disrupted macrophage function impairs this balance, reducing pathogen clearance and increasing tissue damage. To address this, we developed a mathematical model integrating ordinary differential equations (ODEs) and a feedback control framework to design targeted interventions that promote healing. Grounded in the current knowledge of immune cell behavior and signaling, our model highlights macrophage-mediated regulation as a critical driver of infection outcomes. With model-based analysis and a biological understanding about the system dynamics, we designed IL-6-responsive feedback controllers to enhance M1 macrophage-driven pathogen clearance. Simulation results confirmed the efficacy of the controllers in regulating the septic conditions, showing a success of up to 95% in resolving infections when regulating multiple reactions simultaneously. Numerical analysis further demonstrated the robustness of the controllers to biological variabilities and the presence of a secondary infection. We anticipate findings from this work to guide future efforts in designing biological controllers to modulate sepsis-induced inflammation toward a regulated and pro-resolving state.

DOI: https://doi.org/10.1021/acsomega.5c12020