bims-traimu 2026-08-23 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–08–23
ten papers selected by
Yantong Wan, Southern Medical University

Metabolic-epigenetic rewiring of CCR5hi monocytes sustains long-term trained immunity against lethal sepsis.
Harnessing trained immunity for next-generation vaccines: from rational adjuvant design to self-adjuvanting antigens.
Gut-derived small extracellular vesicles support trained innate immune tolerance in murine microglial cells.
The potential role of trained immunity in HIV-associated atherosclerotic cardiovascular disease: mechanisms and therapeutic implications.
Androgen signaling via sympathetic neurons regulates allergic pulmonary inflammation.
DDX3x Regulates NINJ1 Transcription via Histone Lactylation in Sepsis Associated-Acute Kidney Injury.
Mitochondrial profiling across macrophage states reveals inhibition of IL-4/IL-13 reprogramming by the integrated stress response.
Nuclear receptor Nur77 resolves the inflammatory response of macrophages primarily by regulating expression of AP-1 transcription factors and their target genes.
Splenic PD-L1+ Myeloid-Derived Suppressor Cells Induce Contact-Dependent Alveolar Macrophage Dysfunction in Early Sepsis.
Quantitative Modeling of TLR Signaling Reveals Missing Negative Feedback Guiding Identification of TANK-IKKε Checkpoint.

Sci Adv. 2026 Aug 21. 12(34): eaee1634

Metabolic-epigenetic rewiring of CCR5hi monocytes sustains long-term trained immunity against lethal sepsis.

Lingqi Xu, Wenyan Hao, Yingyi Yang, Yu Wang, Yaoshuang Li, Yuan Gong, Yifang Ding, Jie Huang, Zhenjiang Bai, Qiang Shan, Rui Kang, Jiang Huai Wang, Haichao Wang, Timothy R Billiar, Jian Wang, Daolin Tang, Huiting Zhou.

Trained immunity enhances innate host defense by endowing monocytes with memory-like properties, yet the underlying integrated metabolic and epigenetic mechanisms remain elusive. Here, we demonstrate that coimmunization with Bacille Calmette-Guérin (BCG) and bacterial lipoprotein (BLP) induces a durable form of trained immunity that provides robust, long-term protection against polymicrobial sepsis from early life into adulthood. Single-cell RNA sequencing revealed that this effect is mediated by an expansion of CCR5hi memory-like monocytes with enhanced antimicrobial capacity. Mechanistically, BCG + BLP vaccination activated the AKT-mTOR-HIF-1α axis, driving glycolytic reprogramming and lactate accumulation. Elevated lactate enhanced KAT2B-dependent histone H3K18 lactylation, an epigenetic mark directly facilitating the transcription of phagocytic and inflammatory genes. In addition, BCG + BLP stimulation of human cord blood mononuclear cells induced CCR5hi monocytes that recapitulated trained immunity features. These findings identify a lactate-KAT2B-H3K18la epigenetic axis that orchestrates the long-term reprogramming of CCR5hi monocytes, highlighting CCR5hi monocytes as a promising therapeutic target for modulating innate immunity against lethal sepsis.

DOI: https://doi.org/10.1126/sciadv.aee1634
Expert Rev Vaccines. 2026 Dec;25(1): 2721724

Harnessing trained immunity for next-generation vaccines: from rational adjuvant design to self-adjuvanting antigens.

Jing Wang, Xiao-Yong Fan, Zhidong Hu.

   INTRODUCTION: The paradigm of trained immunity (TI), a de facto innate immune memory mediated by metabolic and epigenetic reprogramming of innate leukocytes, has expanded the conceptual framework for rational vaccine adjuvant design. Moving beyond conventional empiricism, TI offers a mechanistic basis that may enhance protection against certain heterologous pathogens, particularly in specific conditions.
AREAS COVERED: This review provides a comprehensive analysis of next-generation adjuvants engineered to induce TI. We outline the core mechanistic foundations encompassing the PI3K/Akt/mTOR/HIF1α-driven immunometabolic switch and ensuing chromatin rewiring, categorize emerging adjuvant strategies from natural TI inducers to synthetic pattern-recognition receptor agonists, direct metabolic-epigenetic modulators, and self-adjuvanting antigens, examine the enabling role of nanotechnology in achieving spatiotemporal control, and discuss translational roadmaps, safety considerations, and pivotal challenges.
EXPERT OPINION: TI-inducing adjuvants provide a mechanistic basis for bridging innate and adaptive immunity and represent a promising direction for next-generation vaccine development. Realizing their full potential will require resolving critical challenges in precision-tunability, host heterogeneity, and durability of the trained state, alongside defining validated correlates of protection. The convergence of systems immunology and advanced delivery platforms might accelerate the transition from concept to clinical vaccines, and contribute to the improved preparedness against infectious and noninfectious diseases.

Keywords:  Trained immunity; adjuvant; epigenetic remodeling; innate immune memory; metabolic reprogramming; self-adjuvanting antigen; vaccine

DOI:  https://doi.org/10.1080/14760584.2026.2721724
Front Immunol. 2026 ;17 1858954

Gut-derived small extracellular vesicles support trained innate immune tolerance in murine microglial cells.

Trim Lajqi, Natascha Köstlin-Gille, Cahit Birdir, Janine Hebel, Ilir Miftari, Reinhard Bauer, Sotirios G Zarogiannis, Charlotta Funaya, Christian Gille, Stefanie Dietz-Ziegler.

   Introduction: Microglia are the resident immune cells of the central nervous system (CNS) that maintain tissue homeostasis and contribute to the pathogenesis of neuroinflammatory disorders. As innate immune cells, microglia can acquire memory-like states that exert long-term effects on CNS function and disease susceptibility. Increasing evidence highlights a dynamic interaction between the gut microbiota and the CNS, shaping microglial maturation and responsiveness throughout life. In addition to soluble microbial metabolites, gut-derived extracellular vesicles (EVs), including vesicles of microbial origin, have emerged as important mediators of microbiota-host communication capable of modulating brain homeostasis and inflammatory signaling; however, their role in programming microglial immune memory remains unclear.
Methods: Here, we examined whether gut-derived small EVs influence memory-like features of primary murine microglia in vitro. Microglia were primed with small EVs followed by a secondary lipopolysaccharide (LPS) challenge, and inflammatory signaling, metabolic activity, epigenetic markers, and effector functions (migration and phagocytosis) were assessed.
Results: Small EV priming followed by secondary LPS challenge induced a trained innate immune tolerance phenotype characterized by reduced pro-inflammatory mediator release and attenuated TLR2/4-MyD88-p38 MAPK signaling. This tolerant state was accompanied by suppressed glycolytic activity and decreased levels of activating histone H3 marks, indicating coordinated metabolic and epigenetic reprogramming. Notably, despite diminished inflammatory signaling, small EV-primed microglia displayed enhanced migratory and phagocytic capacities associated with increased ERK1/2 activation.
Discussion: Together, these findings indicate that gut-derived small EVs can imprint memory-like programs in microglia that restrain inflammatory activation while preserving essential effector functions in vitro, suggesting a mechanism by which microbiota-brain communication may shape neuroinflammatory responses.

Keywords:  epigenetics; extracellular vesicles; gut; inflammation; metabolism; microglia; migration; phagocytosis

DOI:  https://doi.org/10.3389/fimmu.2026.1858954
Front Immunol. 2026 ;17 1918068

The potential role of trained immunity in HIV-associated atherosclerotic cardiovascular disease: mechanisms and therapeutic implications.

Jinchuan Shi, Rongrong Zheng, Zhongdong Zhang.

   Background: People living with HIV (PLWH) exhibit a markedly elevated risk of developing atherosclerotic cardiovascular disease (ASCVD), a phenomenon not entirely attributable to conventional risk factors, thereby indicating the existence of an immune-mediated residual risk. Trained immunity may represent a critical underlying mechanism.
Objective: This review explores the potential of HIV infection-induced trained immunity, examining its underlying mechanisms and its role in the pathophysiology of ASCVD.
Methods: PubMed databases were searched for articles on the association between trained immunity and HIV infection and ASCVD.
Results: HIV triggers trained immunity through various mechanisms: viral proteins like Nef reprogram monocytes, microbial translocation via LPS activates the TLR4-NF-κB pathway, CMV co-infection boosts T-cell activity, and IgA-ADCP causes cross-activation. Some ART regimens (PI/INSTI) promote metabolic training, while CCR5 antagonists may counteract it. Clinical studies and the REPRIEVE trial show immune training markers (sCD14, sCD163) are linked to coronary issues and cardiovascular events, with statins unable to fully reduce monocyte/macrophage inflammation. Strategies include metabolic interventions, anti-IL-1β therapy, epigenetic drugs, optimizing ART, and nanobiological. Importantly, this review distinguishes between canonical innate trained immunity-driven by monocytes, macrophages, and vascular cells-and T-cell immunometabolic dysfunction, which, while coexisting in HIV infection, represents a distinct adaptive immune process. The former is our primary mechanistic focus for ASCVD.
Conclusion: Trained immunity plays a pivotal role in the residual risk associated with HIV-associated ASCVD. From a mechanistic perspective, trained monocytes and macrophages contribute to foam cell formation by hindering cholesterol efflux. Concurrently, trained endothelial cells maintain vascular inflammation and enhance monocyte adhesion, collectively expediting the progression of plaque development. Elucidating the underlying regulatory mechanisms and undertaking intervention trials constitute prospective avenues for translational research.

Keywords:  HIV; atherosclerosis cardiovascular disease; mechanisms; therapeutic implications; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2026.1918068
Sci Immunol. 2026 Aug 21. 11(122): eaed0186

Androgen signaling via sympathetic neurons regulates allergic pulmonary inflammation.

Xiaofan Tu, Hongjie Chen, Xiaoran Ma, Chantal Donovan, Jing Yang.

Sex differences in the rates of asthma onset and remission suggest that sex hormones may play an important role in the pathogenic mechanism underlying certain forms of asthma. Here, we demonstrate that increased endogenous androgen production in male mice can mitigate pulmonary type 2 inflammation after repeated allergen exposures during early life. Building on previous work showing that immune cells can respond to androgen signaling, we report that androgens also promote pulmonary sympathetic innervations, which can dampen type 2 inflammation via the neurotransmitter norepinephrine. Ablation of the androgen signal in sympathetic neurons is sufficient to disturb the establishment of sympathetic structures in the lungs of male mice, thereby amplifying type 2 inflammatory responses to allergens. Thus, an endocrine-neuroimmune axis contributes to the sexual dimorphism of allergic asthma during development.

DOI: https://doi.org/10.1126/sciimmunol.aed0186
Adv Sci (Weinh). 2026 Aug 17. e76979

DDX3x Regulates NINJ1 Transcription via Histone Lactylation in Sepsis Associated-Acute Kidney Injury.

Hongyu Liang, Jihong Jiang, Huanxin Yin, Chunyan Liu, Hongjun Huang, Yan Luo, Minmin Zhu, Qiuyun Wang.

  Sepsis associated-acute kidney injury (SA-AKI), a severe complication of sepsis, is characterized by impaired tubular injury that can ultimately cause renal failure and patient mortality. Both histone and non-histone lactylation and cellular PANoptosis have been implicated in the pathogenesis of SA-AKI. In this study, we investigated how lactylation in histone H3 at lysines 9, 18, and 27 (H3K9/18/27la) modulates PANoptosis in SA-AKI. Our findings revealed that lactate triggers PANoptosis by promoting H3K9/18/27la through the activation of Ninjurin-1 (NINJ1) gene transcription in SA-AKI. Notably, NINJ1, a membrane protein, is also lactylated at residues K111 (K111la) and K114 (K114la) in lipopolysaccharides (LPS)-induced HK-2 cells. NINJ1-K111la mediates plasma membrane localization, thereby promoting cell death. Notably, we identified DEAD (Asp-Glu-Ala-Asp)-box helicase 3x (DDX3x), a previously unreported delactylase capable of regulating H3K9/18/27la levels, which influences NINJ1 transcription and PANoptosis. Furthermore, we developed Odetiglucan (Ode), a novel agonist targeting DDX3x delactylase function. Application of Ode in cecum ligation and puncture (CLP) mice or LPS-induced HK-2 cells significantly reduced H3K9/18/27la levels, inhibited NINJ1 transcription and PANoptosis, and alleviated SA-AKI progression. In summary, DDX3x, function as a delactylase, regulates PANoptosis by influencing H3K9/18/27la. Thus, enhancing the delactylase activity of DDX3x may represent a potential therapeutic strategy for SA-AKI.

Keywords:  cell biology; histone H3; membrane protein; programmed cell death

DOI:  https://doi.org/10.1002/advs.76979
Sci Adv. 2026 Aug 21. 12(34): eaed6318

Mitochondrial profiling across macrophage states reveals inhibition of IL-4/IL-13 reprogramming by the integrated stress response.

Joan Blanco-Fernandez, Miriam Lisci, Mads M Foged, Chloé Chapuis, Tim Pflästerer, Tatjana Kleele, Alexis A Jourdain.

Mitochondria drive cellular reprogramming by integrating metabolism and signaling. In macrophages, mitochondria are central to immunometabolic responses to external cues, but the extent to which they are remodeled and participate in macrophage reprogramming remains unclear. Here, we integrate transcriptomics with whole-cell and purified mitochondrial proteomics to profile lipopolysaccharide (LPS)/interferon-γ (IFN-γ)- and interleukin-4 (IL-4)/IL-13-stimulated macrophages. We reveal a notable disconnect between mitochondrial transcript and protein levels following either stimulus and a signal transducer and activator of transcription 6 (STAT6)-dependent increase in mitochondrial DNA (mtDNA) expression and intramitochondrial translation in IL-4/IL-13 macrophages. We demonstrate that pharmacological inhibition of mitochondrial translation or individual respiratory chain complexes variably impairs reprogramming, whereas ATP synthase inhibition uniquely triggers a heme-regulated inhibitor (HRI)-dependent integrated stress response (ISR) through mitochondrial hyperpolarization, thereby preventing IL-4/IL-13 reprogramming. Mechanistically, we show that restoring mitochondrial membrane potential or inhibiting the ISR rescues IL-4/IL-13-mediated reprogramming. Together, we identify mtDNA expression, intramitochondrial translation, and mitochondrial membrane potential as critical, drug-sensitive determinants of the IL-4/IL-13 response.

DOI: https://doi.org/10.1126/sciadv.aed6318
Nucleic Acids Res. 2026 Aug 10. pii: gkag808. [Epub ahead of print]54(15):

Nuclear receptor Nur77 resolves the inflammatory response of macrophages primarily by regulating expression of AP-1 transcription factors and their target genes.

Sanne C Lith, Sebastian Gregoricchio, Claudia M van Tiel, Ingeborg van der Made, Beatriz M Freire, Simon Linder, Sanne Jacobs, Onno Bleijerveld, Liesbeth Hoekman, Guglielmo L Alonzo, Wilbert Zwart, Marten A Hoeksema, Carlie J M de Vries.

The nuclear receptor Nur77 plays a crucial, protective role in chronic inflammatory diseases and deficiency of Nur77 in macrophages results in excessive pro-inflammatory cytokine secretion. Previous research suggested that Nur77's regulatory function in inflammation is due to repression of the pro-inflammatory transcription factor NF-kB, but the underlying mechanism remains unclear. To address this, we applied a genome-wide, multi-omics approach in LPS-stimulated RAW264.7 macrophages with inducible Nur77 expression. Key findings were validated in wild-type and Nur77-deficient bone marrow-derived macrophages. We show that Nur77 suppresses the expression of inflammatory genes through a dual mechanism wherein Nur77 acts as a repressor of AP-1 targets at two levels: first, Nur77 occupies regulatory elements proximal to AP-1 target genes through AP-1 motifs and second, Nur77 regulates the expression of AP-1 family members themselves. These repressive activities of Nur77 result in diminished RNA Pol II on AP-1 genes and their targets. The first zinc finger of the Nur77 DNA-binding domain is required to reduce AP-1 activity. In summary, Nur77 represses macrophage inflammation through regulation of both immediate-early AP-1 expression, as well as inhibition of AP-1-driven gene programs.

DOI: https://doi.org/10.1093/nar/gkag808
Research (Wash D C). 2026 ;9 1407

Splenic PD-L1+ Myeloid-Derived Suppressor Cells Induce Contact-Dependent Alveolar Macrophage Dysfunction in Early Sepsis.

Bing Xie, Mengqi Han, Xiaoyue Wen, Yin Yuan, Hong Qi, Yujing Zhang, Xin Wang, Zifan Zhen, Mengyuan Wang, Xinyu Zhang, Tingting Jin, Xueqiang Sun, Zhigang Wang, Xiaofeng Li, Shiying Yuan, Jiancheng Zhang, You Shang.

Sepsis frequently leaves patients with persistent immune impairment that contributes to late mortality, yet the anatomical routes that transmit this response to the lung remain poorly defined. Here, we identify the spleen as a key extramedullary hub orchestrating pulmonary immune paralysis through a spleen-lung axis. Mechanistically, splenic programmed death-ligand 1 (PD-L1)+ polymorphonuclear myeloid-derived suppressor cells undergo TFDP1-driven expansion and migrate to the lungs via CXCL2/CXCR2 signaling, establishing an interorgan immunosuppressive circuit. In the lung, these cells reprogram alveolar macrophages through programmed death-1 (PD-1)-dependent checkpoint signaling, inducing a dysfunctional state characterized by impaired antibacterial responses and enrichment of complement and immune checkpoint pathways. Genetic or pharmacologic disruption of the PD-L1-PD-1 axis restores macrophage function and improves pulmonary host defense in experimental sepsis. Together, these findings define a mechanistic link between splenic myelopoiesis and distal lung immune paralysis.

DOI: https://doi.org/10.34133/research.1407
bioRxiv. 2026 Aug 16. pii: 2026.08.03.742528. [Epub ahead of print]

Quantitative Modeling of TLR Signaling Reveals Missing Negative Feedback Guiding Identification of TANK-IKKε Checkpoint.

Nathan P Manes, Fengkai Zhang, Bin Lin, Jing Sun, Sergio A Hassan, Anthony A Armstrong, Yuting Shao, Jessica M Calzola, Pauline R Kaplan-Stafford, Rachel A Gottschalk, Matthew J Marino, Doeun Kim, Ronald N Germain, Iain D C Fraser, Martin Meier-Schellersheim, Aleksandra Nita-Lazar.

Toll-like receptor (TLR) signaling must be activated rapidly and then terminated to support host defense without sustained inflammation. We developed a rule-based model of mouse macrophage TLR4 signaling at the molecular-interaction level using measured protein copy numbers, RNA-seq-based abundance estimates, literature- and structure-informed reaction rates, and 979 dynamic experimental constraints. The trained model reproduced much of the TLR4-induced NF-κB and MAP kinase response but consistently failed to capture deactivation of MyD88, TRAF6-associated species, and IKKα/β. The recurrent model failure conveyed important biological information, localizing missing regulation to the proximal MyD88-IRAK-TRAF6 module and guiding experimental evaluation of IKKε and its scaffold TANK. Loss of IKKε enhanced transcriptional, cytokine, MAP kinase, and NF-κB responses to MyD88-specific TLR ligands. TANK deficiency produced a similar cellular phenotype and abolished stimulus-induced IKKε phosphorylation. Deficiency of either protein increased IRAK1 and TRAF6 ubiquitination without increasing MyD88 ubiquitination, placing the inhibitory checkpoint at or immediately downstream of the IRAK1-TRAF6 ubiquitin-signaling node. Overlapping but non-identical in vivo phenotypes further supported a shared regulatory axis with additional protein-specific functions. Our study presents a model-experiment discovery cycle where quantitative pathway discordance identifies missing biology and reveals a TANK-dependent IKKε checkpoint that restrains MyD88-driven inflammation.

DOI: https://doi.org/10.64898/2026.08.03.742528