bims-traimu 2025-11-30 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–11–30
ten papers selected by
Yantong Wan, Southern Medical University

Epigenetic programming reshapes innate immune memory: decoding the molecular imprint of gouty inflammation.
Interleukin-38 is a negative regulator of trained immunity-A retrospective multi-omics study.
Polysaccharide Adjuvants as Innate Immune Trainers: Bridging Pattern Recognition Receptor (PRR) Activation and Metabolic Reprogramming for Synthetic Vaccine Design.
Microglial Nrf2 Functions as a Cell-Autonomous Regulator of Neuroinflammation and Trained Immunity in the Aging Brain.
β-Glucan pretreatment activates lectin pathway to maintain the function of intestinal Th17 cells for infectious enteritis protection.
A metabolic reprogramming and trained immunity hydrogel mimic cluster missiles to eliminate infection and treat infected diabetic wounds.
Itaconate transport across the plasma membrane and Salmonella-containing vacuole via MCT1/4 modulates macrophage antibacterial activity.
Inhibiting peripheral serotonin activates liver AMPK and reduces monocyte-derived macrophages and fibrosis.
Accurate processing of ultra-short immune signals by single macrophages.
Transcriptional condensates at super-enhancers mediate pH-dependent transcriptional control in innate immunity.

Front Pharmacol. 2025 ;16 1678958

Epigenetic programming reshapes innate immune memory: decoding the molecular imprint of gouty inflammation.

Wenjie Su, Yifan Lu, Zhiqiang Luo, Hui Xiong.

  Gout is an inflammatory joint disease caused by abnormal uric acid metabolism, characterized by the deposition of urate crystals in joints and surrounding tissues, leading to acute or chronic inflammatory responses. The etiology and pathogenesis of gout are complex, and there is currently a lack of ideal therapeutic drugs and treatment strategies. Epigenetic modifications influence and regulate gene function and characteristics through mechanisms such as DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA, thereby exerting significant effects on the physiological and pathological states of the body. Recently, epigenetic modifications and trained immunity in gout have garnered increasing research interest. Epigenetic modification-mediated trained immunity represents a frontier area in the study of gout pathogenesis. This review summarizes the latest findings on the role and regulatory mechanisms of epigenetic modifications in the development of gout, as well as the role of epigenetic remodeling-mediated trained immunity in gout and the potential applications of epigenetic intervention strategies in gout, providing new insights into the relationship between persistent inflammation, epigenetics, and innate immune memory in gout.

Keywords:  DNA methylation; acetylation; epigenetic reprogramming; gout; histonemodification; non-coding RNA; trained immunity

DOI:  https://doi.org/10.3389/fphar.2025.1678958
iScience. 2025 Nov 21. 28(11): 113758

Interleukin-38 is a negative regulator of trained immunity-A retrospective multi-omics study.

Lisa U Teufel, Vasiliki Matzaraki, Lukas Folkman, Dennis M de Graaf, Rob Ter Horst, Simone J C F M Moorlag, Jéssica C Dos Santos, Catharina M Mulders-Manders, Thomas Krausgruber, Charles Dinarello, Mihai G Netea, Leo A B Joosten, Rob J W Arts.

  Trained immunity is a long-lasting innate immune cell phenotype with benefits in infection control and recognized anti-cancer effects. Conversely, inappropriately induced trained immunity contributes to pathological inflammation, warranting the exploration of regulatory pathways. We explore interleukin-38 (IL-38) as a regulator of trained immunity in vivo in a cohort of 325 healthy adults vaccinated with Bacillus Calmette-Guérin (BCG). Using multi-omics profiling, we find that IL-38 is negatively associated with trained immunity on metabolic and epigenetic level. Genetic variants in IL1F10, encoding for IL-38, further link IL-38 to diminished training responses. These associations were validated in human and murine models. We confirmed that IL-38 functionally impairs anti-microbial traits of trained immunity in trained immunity-infection models in vivo (IL-38KO mice) and in vitro (human monocytes). Our study therefore suggests that IL-38 endogenously regulates the induction of trained immunity in humans in vivo.

Keywords:  Immune response; Immunity; Omics

DOI:  https://doi.org/10.1016/j.isci.2025.113758
Adv Sci (Weinh). 2025 Nov 25. e09022

Polysaccharide Adjuvants as Innate Immune Trainers: Bridging Pattern Recognition Receptor (PRR) Activation and Metabolic Reprogramming for Synthetic Vaccine Design.

Jeong Hyun Moon, May Thazin Phoo, Yubin Kim, Jinsung Ahn, April Kim, Jutaek Nam, Soo-Hong Lee, James J Moon, Sejin Son.

  The concept of trained immunity has redefined the understanding of innate immune memory and opened new opportunities for vaccine design. Polysaccharides, as naturally occurring pathogen-associated molecular patterns (PAMPs), can activate pattern recognition receptors (PRRs) and induce durable immunomodulatory effects. This review examines the historical context of microbial immunotherapy, beginning with Coley's toxin, and traces its evolution toward the rational use of polysaccharides as vaccine adjuvants. Their mechanisms of action, ranging from PRR engagement to metabolic and epigenetic reprogramming, are discussed to support both innate training and adaptive immune activation. Emphasis is placed on how these materials interact with biological barriers, influence antigen processing, and enhance lymph node trafficking. By analyzing the immunological functions and material properties of β-glucan, mannan, alginate, hyaluronic acid, chitosan, and others, the potential of polysaccharide-based platforms is highlighted to improve the efficacy and breadth of synthetic vaccines.

Keywords:  PAMP‐PRR; immune engineering; immunoadjuvant; polysaccharide; trained immunity

DOI:  https://doi.org/10.1002/advs.202509022
FASEB J. 2025 Nov 30. 39(22): e71244

Microglial Nrf2 Functions as a Cell-Autonomous Regulator of Neuroinflammation and Trained Immunity in the Aging Brain.

Hallel C Paraiso, Jui-Hung Jimmy Yen, Barbara A Scofield, Ping-Chang Kuo, Fen-Lei Chang, I-Chen Ivorine Yu.

Aging is the primary risk factor for Alzheimer's disease (AD) and related dementias, with chronic neuroinflammation contributing to disease progression. Microglia, the brain's resident immune cells, undergo age-associated changes that disrupt neuroimmune homeostasis and exacerbate neuroinflammation. The transcription factor Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2), a master regulator of cellular stress responses, has an undefined role in microglial aging. We demonstrate that Nrf2 mRNA expression and protein decline in aged microglia, coinciding with increased neuroinflammation and antigen presentation. Global Nrf2-deficient (Nrf2-/-) mice exhibit amplified microglial activation, elevated MHC class II-related CD74 expression, and enhanced infiltration of peripheral CD4+ T cells into the brain. Nrf2-/- microglia adopt a disease-associated microglia (DAM)-like phenotype, characterized by upregulated activation markers and transcriptional reprogramming. Functionally, Nrf2 loss impairs motor learning and cognitive performance in middle-aged mice. To dissect the role of microglial Nrf2, we generated microglia-specific Nrf2 knockout (MG-Nrf2-KO) mice using a Cx3cr1-CreERT2 system. MG-Nrf2-KO mice exhibit exaggerated microglial immune training characterized by elevated brain TNFα and IL-1β production upon secondary LPS challenge, despite preserved peripheral immune tolerance. The heightened training response is accompanied by reduced IL-10 expression in MG-Nrf2-KO brains, indicating impaired anti-inflammatory counter-regulation. Ex vivo restimulation confirms that Nrf2-deficient microglia intrinsically produce elevated pro-IL-1β protein upon rechallenge, establishing Nrf2 as a cell-autonomous regulator of microglial immune memory. These findings identify Nrf2 as an intrinsic regulator of microglial immune memory and neuroinflammatory restraint. Modulating Nrf2 signaling in microglia may offer a therapeutic strategy to mitigate chronic neuroinflammation and cognitive decline in aging and neurodegeneration.

DOI: https://doi.org/10.1096/fj.202501457RR
Zool Res. 2025 Nov 18. pii: 2095-8137(2025)06-1411-14. [Epub ahead of print]46(6): 1411-1424

β-Glucan pretreatment activates lectin pathway to maintain the function of intestinal Th17 cells for infectious enteritis protection.

Yanbo Zhao, Xiaochuan Mei, Jin Yang, Zhuang Wang, Qin Liu, Yuanxing Zhang, Dahai Yang.

  Enteritis, involving inflammation of the small intestine, is often accompanied by immune cell dysfunction during intestinal infections. Immunomodulatory β-glucans (BGs) have recently been shown to support antibacterial immune responses through the induction of trained immunity. However, little is known about the potential role of BG pretreatment in protecting against infectious enteritis in teleost fish. In this work, by establishing an adult zebrafish enteritis model via infection with the fish pathogen Edwardsiella piscicida and pretreating it with BGs, we demonstrated that such pretreatment confers protection against infectious enteritis, accompanied by reduced production of proinflammatory cytokines. Specifically, we found that BG pretreatment could amplify intestinal lectin pathway-associated complement activation to ameliorate the infectious enteritis. Moreover, through comprehensive RNA-seq analysis of immune cell marker genes in zebrafish, we revealed that the lectin pathway amplification by BG pretreatment modulated the responsiveness of intestinal Th17 cells, which was essential for the protection against infectious enteritis. Collectively, these findings identify the intestinal lectin pathway as a potential mediator of the effects of BG pretreatment and reveal its role in maintaining the function of Th17 cells in zebrafish. This suggests that harnessing BG-induced trained immunity might represent a promising therapeutic strategy against infectious enteritis in teleost.

Keywords:  Edwardsiella piscicida; Infectious enteritis; Lectin pathway; Th17 cell; Zebrafish; β-Glucan

DOI:  https://doi.org/10.24272/j.issn.2095-8137.2025.117
J Nanobiotechnology. 2025 Nov 28. 23(1): 749

A metabolic reprogramming and trained immunity hydrogel mimic cluster missiles to eliminate infection and treat infected diabetic wounds.

Zirui Yu, Zhenyi Chen, Hongxia Xie, Ping Duan, Haoxing Hu, Hao Zhang, Xin Ye, Yongle Yu, Yannan Cheng, Zhenyu Pan.

  Excessive inflammation, infection, persistent reactive oxygen species (ROS) accumulation, hyperglycemia, and vascular lesions in diabetic chronic wounds severely impair healing. Currently, there is no treatment regimen available to improve the complex microenvironment of such wounds. We have designed a comprehensive microenvironment intervention system, namely the composite dressing CVCeCG. The injectability, self-healing properties, and tissue adhesion of hydrogel make it an ideal physical barrier. The CVCeCG hydrogel incorporates a photothermal therapy (PTT) strategy, enabling photothermal activation of a missile-like bactericidal program to eliminate infections rapidly. Additionally, CVCeCG hydrogel remodels the immune microenvironment, constructs a dynamic regulatory network of epidermal/dermal cells, macrophages, and blood vessels through immune training and metabolic reprogramming. Even after the dressing is removed, it can still promote wound healing and has long-term effects. Furthermore, this hydrogel dressing alleviates wound hypoxia and reduces ROS levels, thereby further mitigating inflammation and promoting tissue repair. In the diabetic rat model with MRSA-infected wounds, the CVCeCG hydrogel significantly eliminated infection, reduced local inflammatory responses and ROS levels, and established a mutually supportive cycle between improved immune microenvironment and angiogenesis, thereby promoting wound healing. In summary, this work provides significant insights into the use of photothermal therapy to eliminate bacteria and improve the immune microenvironment through immune training and metabolic reprogramming, offering new strategies for comprehensively improving the microenvironment of chronic wounds in diabetes. A hydrogel (CMC-PDA/GEL) was created by combining gelatin (GEL) with catechol-modified carboxymethyl cellulose (CMC-DA). Composite hydrogel dressings in CVCeCG were created by adding polycaprolactone microspheres loaded with calcium peroxide (CPO@PCL) or vancomycin (Van@PCL) and cerium oxide nanoparticles (CeNPs) to CMC-PDA/GEL. This hydrogel can mimic missiles to eliminate infections quickly, remodel the local immune microenvironment by training the immune system and metabolic reprogramming, and clear ROS, establishing a comprehensive microenvironment intervention system, which helps wounds heal.

Keywords:  Comprehensive microenvironment intervention system; Hydrogel dressing; Infected diabetic wounds; Metabolic reprogramming; Synergistic photothermal therapy strategy; Trained immunity

DOI:  https://doi.org/10.1186/s12951-025-03818-9
Nat Commun. 2025 Nov 26. 16(1): 10551

Itaconate transport across the plasma membrane and Salmonella-containing vacuole via MCT1/4 modulates macrophage antibacterial activity.

Qingcai Meng, Chengxi Li, Yuping Cai, Ying Chen, Xiaoqing Chen, Xin Wang, Biling Zhang, Yue Zhang, Feng Liu, Meixin Chen.

Itaconate accumulates in macrophages upon bacterial infection, and manifests antibacterial activity. Convincing evidence substantiates that itaconate is transported across the plasma membrane and vacuolar membrane, but the molecular bases underlying bidirectional transport of itaconate across membranes and its effects on intracellular bacterial replication are less known. Here, we identify MCT1 and MCT4 as bidirectional transporters of itaconate. In addition to modulating itaconate concentration as transporters at the plasma membrane, MCT1 and MCT4 function as itaconate transporters at Salmonella-containing vacuole (SCV). Upon Salmonella infection, MCT1 and MCT4 transport itaconate into SCV facilitated by RAB32. Itaconate is also secreted out of cells through MCT1 and MCT4 as the infection persists. The suppression of MCT1 and MCT4-dependent itaconate secretion increases the overall concentration of itaconate and the proportion of itaconate-targeted Salmonella intracellularly, consequently inhibiting Salmonella replication. Our study thus offers valuable insights into itaconate transport during bacterial infection and provides proof of principle for the development of itaconate-dependent therapeutic strategies.

DOI: https://doi.org/10.1038/s41467-025-65582-6
Cell Rep. 2025 Nov 26. pii: S2211-1247(25)01379-8. [Epub ahead of print]44(12): 116607

Inhibiting peripheral serotonin activates liver AMPK and reduces monocyte-derived macrophages and fibrosis.

Battsetseg Batchuluun, Tinne Thoné, Andre Djalalvandi, Russta Fayyazi, Parneet Deo, Julian M Yabut, Sara Maggiore, Bavo Vanneste, Jaya Gautam, Logan K Townsend, Elham Ahmadi, Maria Joy Therese Jabile, Marisa Morrow, Eric M Desjardins, Evangelia E Tsakiridis, Sonia Rehal, Waliul I Khan, Dongdong Wang, Charlotte L Scott, Gregory R Steinberg.

  Monocyte-derived liver macrophages are critical in the pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis, but their recruitment mechanisms remain unclear. Serotonin (5-hydroxytryptamine [5HT]) is a conserved monoamine synthesized by tryptophan hydroxylase 1 (Tph1) in peripheral tissues and Tph2 in the brain. We show that, in mice housed at thermoneutrality and fed a high-fat, high-fructose diet, inhibition of peripheral serotonin (pe5HT) through genetic deletion of Tph1 prevents MASH independent of reduction in body weight. Liver flow cytometry and single-nucleus sequencing showed reduced pro-inflammatory Ly6Chigh monocytes, monocyte-derived Kupffer cells (moKCs), and lipid-associated macrophages (LAMs) in Tph1 knockout (KO) mice. Tph1 deletion also decreased circulating monocytes, specifically Ly6Chigh monocytes. A single 5HT injection increased Ly6Chigh monocytes, while Tph1 KO mice had reduced monocytes without affecting bone marrow monocytes. Mechanistically, serotonin inhibition increases liver AMP-activated protein kinase (AMPK) activity, and this is important for reducing CCL2 and monocyte recruitment. These findings link two ancient energy sensors, 5HT and AMPK, with obesity-associated liver fibrosis.

Keywords:  AMPK; CP: Immunology; CP: Metabolism; MASH; immunometabolism; liver fibrosis; macrophage; metabolic syndrome; monocyte; obesity; serotonin

DOI:  https://doi.org/10.1016/j.celrep.2025.116607
bioRxiv. 2025 Oct 26. pii: 2025.10.26.684377. [Epub ahead of print]

Accurate processing of ultra-short immune signals by single macrophages.

Gabriel Mercado-Vasquez, James Vizzard, Betul Celiker, Junjie Xia, Andrew Wang, Abinash Padhi, Savas Tay.

Accurately interpreting short-lived signals is challenging within noisy cellular microenvironments. It is not known if cells can distinguish different signaling molecules under transient exposure. Here, we explored the temporal limits of signal detection by single macrophages. Microfluidic experiments monitoring NF-kB dynamics showed that macrophages strongly respond even to 1-second pulses of cytokine and pathogen ligands. Information theory showed that short-pulse response is highly specific to the stimulating ligand, comparable to that under long-term stimulation. Macrophages were mainly sensitive to the duration of cytokines, and the dose of pathogen ligands. Stimulus duration altered the ranking of response strengths among different pathogenic ligands. Mathematical modeling showed that receptor cooperativity is crucial for robust responses to transient signals, while receptor pathway variability leads to accurate signaling in fluctuating environments. These findings demonstrate that dynamic transcription factor specificity is preserved across varying signal durations and uncover network-level mechanisms that accurately distinguish transiently encountered threats.

DOI: https://doi.org/10.1101/2025.10.26.684377
bioRxiv. 2025 Oct 30. pii: 2025.10.29.685293. [Epub ahead of print]

Transcriptional condensates at super-enhancers mediate pH-dependent transcriptional control in innate immunity.

Shengyuan Wang, Zhongyang Wu, Zhe Zhong, Xu Zhou, Chongzhi Zang.

Tissue acidification is a common feature of hypoxia, inflammation and solid tumor. Acidic pH regulates innate immune response in macrophages by weakening BRD4-containing transcriptional condensates. Yet how disruption of transcriptional condensates leads to gene-specific regulation of immune programs remain unclear. Here, we integrated ATAC-seq, ChIP-seq, and RNA-seq of primary murine macrophages and performed integrative epigenomics analyses to identify transcriptional regulators (TRs) with pH-sensitive regulatory potential and association to BRD4-dependent transcriptional condensates. We determined pH-dependent super-enhancers (SEs) by extended profiles of BRD4 binding and h3K27ac marks. We found RELA, IRF family, and STAT family as candidate TRs enriched at BRD4-associated, pH-sensitive SE regions. RELA and IRF3 preferentially occupied BRD4-associated and pH-sensitive SEs, and displayed markedly reduced binding under acidic conditions, aligning with BRD4 occupancy change. Correspondingly, immune-response genes within BRD4-associated, pH-sensitive SE regions, including Ch25h , Acp2 , Gda , and Ifit family, were significantly higher expressed at pH 7.4 than at pH 6.5. Together, these results reveal a set of TRs involved in BRD4-associated, pH-sensitive transcriptional condensates that coordinate macrophage gene activation under physiological conditions, providing mechanistic insight into how acidic stress modulates transcriptional condensates and immune responses.

DOI: https://doi.org/10.1101/2025.10.29.685293