bims-traimu 2026-07-26 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–07–26
ten papers selected by
Yantong Wan, Southern Medical University

Exercise, mitochondrial stress, and trained immunity: metabolic adaptation of innate immunity.
Mycobacterium tuberculosis infection triggers IL-1β-dependent epigenetic training in bystander macrophages.
Microglial states revisited: from homeostasis to disease.
A Novel IDO1/NE Dual Inhibitor, IMM-H018 Prevents the Primary and Secondary Sepsis and Ameliorates the Kidney Injury Through Inhibiting the Cytokine Storm and Microthrombosis, and Reversing Immunosuppression.
4-octyl itaconate alleviates LPS-induced inflammation in Sertoli cells by inhibiting excessive autophagy.
Shielded by the Dead: How Killed Bacteria Shape the Dynamics and Evolution of Innate Immunity.
Toll-like receptor responses are shaped by distinct MAPK activation profiles.
NADPH oxidase 2 (NOX2)-independent inducers of neutrophil extracellular traps promote resolution of chronic inflammation.
Single-cell chromatin state transitions during epigenetic memory formation.
Temporal control of macrophage pro-inflammatory phenotype by a biphasic HIF-1α regulatory program.

Front Immunol. 2026 ;17 1902029

Exercise, mitochondrial stress, and trained immunity: metabolic adaptation of innate immunity.

Enli Xie, Yushan He, Yongjun Sun.

  Traditionally recognized as "cellular powerhouses", mitochondria have gained relevance as pivotal nodes in the integration of metabolism, stress signaling, and innate immunity. In this context, the present work seeks to answer the following question: Does the continuous, exercise-induced mitochondrial stress contribute towards training of innate immune cells by promoting the generation of DAMPs such as mtDNA and succinate? Exercise can be considered as a form of controllable mitochondrial stressor. Mechanistically, the temporary release of mtDAMPs through exercise results in activation of pattern recognition receptors (NLRP3, TLR9, cGAS-STING). Subsequently, there is a metabolic reprogramming event favoring switch from oxidative phosphorylation to aerobic glycolysis along with epigenetic changes (H3K4me3, H3K27ac) priming pro-inflammatory genes for enhanced secondary response. Moderate-intensity exercise develops an immune homeostatic condition with reduced low-grade inflammation and increased reactivity, while sedentary behavior fosters chronic low-grade inflammation, and excessive high-volume exercise can temporarily reduce immune competency. Herein, we present an integrative model where exercise-induced mitochondrial stress as a physiological "training vaccine" to enhance immune surveillance via trained immunity principles. The current model helps differentiate the immune status of elite athletes from sedentary subjects and paves the way for understanding the immunological benefit of exercise prescription in infection prevention, metabolic health, and cancer immunotherapy.

Keywords:  DAMPs; epigenetic reprogramming; exercise immunology; metabolic reprogramming; mitochondrial stress; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2026.1902029
mBio. 2026 Jul 21. e0121426

Mycobacterium tuberculosis infection triggers IL-1β-dependent epigenetic training in bystander macrophages.

Shah-E-Jahan Gulzar, Ibrahim Umar, Bharath Saravanan, Dhruv Sheth, Arif Hussain Najar, Umer Farooq, Sahanawaz Molla, Adithi Ravikumar, Dimple Notani, Varadharajan Sundaramurthy.

  Mycobacterium tuberculosis (Mtb) remodels host cell functions to support its persistence within macrophages. While infected cells have been extensively studied, the responses of uninfected bystander macrophages in the same microenvironment remain poorly understood. Here, we demonstrate that Mtb infection triggers broad epigenetic and transcriptional reprogramming in bystander macrophages, predominantly via interleukin-1β-dependent nuclear factor-κB signaling from infected cells. These bystander cells acquire active chromatin marks, exhibit distinct gene expression profiles, and display enhanced responsiveness to subsequent immune challenges. Functionally, bystander macrophages restrict intracellular Mtb growth and also show increased responsiveness to heterologous stimuli resembling trained immunity. Our findings uncover a previously underappreciated mechanism of intercellular communication during infection, wherein Mtb-infected macrophages prime neighboring uninfected cells for enhanced defense. This work defines cytokine-mediated reprogramming of both infected and bystander cell subpopulations, and identifies bystander cells as active participants in shaping the population-wide host immune landscape. These insights have implications for understanding innate immune memory and developing strategies to modulate host defense in tuberculosis and other infections.
IMPORTANCE: This study reveals an underappreciated role for uninfected bystander macrophages in host defense against Mycobacterium tuberculosis (Mtb). We demonstrate that Mtb-infected macrophages trigger interleukin-1β-mediated epigenetic training in neighboring bystander cells, priming them for enhanced immune responses. These trained macrophages exhibit heightened antimicrobial activity and restrict Mtb growth upon subsequent infection. By uncovering a mechanism through which immune memory-like responses propagate beyond infected cells, our findings redefine the cellular scope of innate immunity during tuberculosis and identify new opportunities to boost host defense through intercellular signaling and epigenetic reprogramming.

Keywords:  H3K27 acetylation; IL-1β; bystander cells; epigenetic modifications; superinfection; trained immunity; tuberculosis

DOI:  https://doi.org/10.1128/mbio.01214-26
Nat Rev Neurosci. 2026 Jul 20.

Microglial states revisited: from homeostasis to disease.

Bart J L Eggen, Susanne M Kooistra.

Microglia, the resident macrophages of the CNS parenchyma, are recognized as highly plastic, transcriptionally diverse cells whose phenotypes are moulded by development, region, sex, age, genotype and environment. Advances in single-cell and single-nucleus transcriptomics, chromatin accessibility profiling, and spatial multi-omics have negated binary frameworks of 'resting versus activated' or 'M1 (pro-inflammatory) versus M2 (anti-inflammatory)' and revealed a multidimensional state space that supports brain development, homeostasis and adaptive responses to perturbation. Building on the foundational concepts of the microglial sensome, homeostatic and disease-associated signatures, microglia exhibit transcriptomic state transitions in neurodegeneration, demyelination, infection and systemic inflammation. Moreover, a mechanistic framework for more 'hidden' microglial states has emerged, in which latent programmes that appear homeostatic at baseline are revealed by challenges and are instructed through innate immune training or tolerance. We argue that these covert reprogrammed states, which are shaped by ageing, genotype, sex, location and prior exposures such as sepsis or viral infection, help explain interindividual variability in disease trajectories. We conclude by outlining priorities for unifying state annotation across species and modalities, and for translating state-resolved insights into biomarkers and interventions.

DOI: https://doi.org/10.1038/s41583-026-01066-w
Adv Sci (Weinh). 2026 Jul 20. e76504

A Novel IDO1/NE Dual Inhibitor, IMM-H018 Prevents the Primary and Secondary Sepsis and Ameliorates the Kidney Injury Through Inhibiting the Cytokine Storm and Microthrombosis, and Reversing Immunosuppression.

Yi Zhou, Xiaodi Zhao, Xiaochen Pan, Zhiling Ma, Huaqing Cui, Hui Wen, Peng Wang, Xiufeng Liao, Kejie Qin, Yuchen Wang, Li Sheng, Sen Zhang.

  Sepsis is characterized by the simultaneous presence of hyperinflammation, immunosuppression, and coagulation abnormalities, making single-target therapies insufficient. In this study, we explored a strategy that concurrently suppresses neutrophil-mediated inflammation and reverses immune dysfunction. Combined treatment with the neutrophil elastase (NE) inhibitor Sivelestat and the indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor Epacadostat showed superior efficacy to either monotherapy in LPS- and CLP-induced septic mice. Based on this concept, a novel dual IDO1/NE inhibitor, IMM-H018, was designed and synthesized. IMM-H018 effectively inhibited both IDO1 and NE activities in vitro and in vivo and significantly improved survival in CLP-induced sepsis. In low-dose LPS models, IMM-H018 reduced systemic inflammation and restored immune function in peripheral blood, thymus, and spleen, outperforming the combination therapy. Furthermore, IMM-H018 alleviated sepsis-associated acute kidney injury by improving renal perfusion and reducing microthrombosis through inhibition of the IDO1-Kyn-AhR-TF pathway. In a two-hit sepsis model, IMM-H018 prevented secondary infection, enhanced bacterial clearance through improved phagocytosis, protected against renal damage, and delayed progression from acute kidney injury to chronic kidney dysfunction. These findings identify IMM-H018 as a promising therapeutic candidate for sepsis and sepsis-associated kidney injury.

Keywords:  Acute kidney injury; IDO1; NE; Sepsis; dual inhibitor; immune suppression

DOI:  https://doi.org/10.1002/advs.76504
Redox Biol. 2026 Jul 17. pii: S2213-2317(26)00306-X. [Epub ahead of print]95 104307

4-octyl itaconate alleviates LPS-induced inflammation in Sertoli cells by inhibiting excessive autophagy.

Yuan Li, Xianglong Wang, Haijuan Yang, Feng Jiang, Meihua Wang, Yue Wang, Dong Niu, Huaming Xi.

  Bacterial orchitis is a major cause of male infertility, yet effective therapies remain limited. Although the itaconate derivative 4-octyl itaconate (4-OI) possesses potent anti-inflammatory properties, its role in testicular inflammation is unclear. Here, we investigated the protective effects and mechanisms of 4-OI in lipopolysaccharide (LPS)-induced inflammatory injury using Sertoli cells and a mouse model of acute orchitis. LPS activated NF-κB/NLRP3 signaling and induced excessive autophagy in Sertoli cells, resulting in oxidative stress, apoptosis, disruption of tight junctions, and functional impairment. 4-OI markedly suppressed NF-κB phosphorylation and NLRP3 activation, reduced mitochondrial oxidative stress, and improved cell viability. Mechanistically, 4-OI inhibited excessive autophagy by downregulating UNC-51-like kinase 1 (ULK1) and autophagy-related proteins, thereby limiting autophagic flux. Consequently, Sertoli cell functional markers, tight junction integrity, and mitochondrial homeostasis were restored. In vivo, 4-OI alleviated testicular histopathological damage, reduced germ cell apoptosis, improved sperm quality, preserved blood-testis barrier integrity, and enhanced spermatogenic activity. Collectively, these findings identify ULK1-associated excessive autophagy as a key mechanism of inflammatory testicular injury and demonstrate that 4-OI protects against orchitis-induced reproductive dysfunction, highlighting its therapeutic potential for inflammation-associated male infertility.

Keywords:  4-octyl itaconate; Autophagy; Inflammation; Sertoli cell; ULK1

DOI:  https://doi.org/10.1016/j.redox.2026.104307
Am Nat. 2026 Aug;208(2): 161-177

Shielded by the Dead: How Killed Bacteria Shape the Dynamics and Evolution of Innate Immunity.

Stephen P Ellner, Nicolas Buchon, Tobias Dörr, Misha I Kazi, Brian P Lazzaro, Alexander Vladimirsky.

  AbstractThe outcome of an infection is determined by the dynamic interplay between microbial growth and host immunity. During a bacterial infection, bacteria killed by innate immune effectors can accumulate as corpses in the extracellular space, where they can continue to bind (and thus sequester) immune effectors. The impacts on infection outcomes of continued biochemical activity ("sponginess") by the dead have been generally overlooked in theoretical and empirical studies of within-host disease dynamics. We develop a mechanism-based mathematical model of within-host dynamics that incorporates host microbial sensing, the production of immune effectors, the interaction of those effectors with microbes, and shutdown of the immune response after an infection has been controlled. Corpse sponginess impedes the host's ability to control infection, but at the same time the rapid mopping up of effectors by bacterial corpses also protects host tissue against autoimmune self-harm from immune effectors still circulating after the infection has been resolved. This dual impact of bacterial sponginess alters the trade-off between damage done by infecting bacteria and autoimmune damage, consequently shifting the evolutionarily optimal immune activation and shutdown kinetics. Thus, the sponginess of bacterial corpses likely shapes both the short-term infection dynamics and the long-term evolution of immune systems.

Keywords:  antimicrobial peptide; host-pathogen interactions; immune system evolution; innate immunity

DOI:  https://doi.org/10.1086/741105
J Immunol. 2026 Jul 10. pii: vkag180. [Epub ahead of print]215(7):

Toll-like receptor responses are shaped by distinct MAPK activation profiles.

Nada Elhadedy, Areej Alotaibi, Lynn McGarry, Ruaidhrí J Carmody.

  Toll-like receptors (TLRs) are key sensors of infection and injury, and are critical inducers of inflammation. TLR-induced activation of the NF-κB and MAPK pathways promotes the secretion of mediators of inflammation such as cytokines and chemokines. Control of cytokine production is critically important, as unnecessary inflammatory responses can lead to tissue damage, while insufficient inflammatory responses can lead to susceptibility to infection. Previous studies showed that TLR4 uses distinct NF-κB and MAPK activation properties to discriminate between low and high concentrations of ligand, triggering cytokine production only at ligand concentrations that activate both pathways. The switch-like activation of MAPKs by TLR4 establishes an inflammatory threshold for ligand concentrations that facilitates threat discrimination. Using murine macrophages, we reveal that MAPK activation properties are TLR-specific, and that switch-like MAPK activation is not a general feature of all TLRs. Consequently, certain TLRs do not have an inflammatory threshold of ligand concentration and may not effectively filter signal from noise. The activation properties of the ERK pathway, rather than messenger RNA levels, dictate the patterns of TNFα cytokine secretion for all TLRs examined. We demonstrate that the TLR4 inflammatory threshold can be modulated by costimulation with granulocyte-macrophage colony-stimulating factor in an ERK-dependent manner. We show that deletion of BCL-3 changes the TLR4-induced ERK pathway activation properties from switch-like to gradual and lowers the activation threshold. We reveal that different TLRs have different capacities to discriminate threats based on ligand concentration, and that ERK pathway activation properties can be altered to change the cellular decision to initiate inflammation.

Keywords:  MAPK; activation thresholds; cytokine; toll-like receptors

DOI:  https://doi.org/10.1093/jimmun/vkag180
Redox Biol. 2026 Jul 15. pii: S2213-2317(26)00301-0. [Epub ahead of print]95 104302

NADPH oxidase 2 (NOX2)-independent inducers of neutrophil extracellular traps promote resolution of chronic inflammation.

M Euler, O Hattab, K Borah Slater, B Golub, R Selin, Z Cheng, Y A Maluje Villanueva, G H Özkan, G Bila, K Dutta, D Weidner, E J Hoffmann, J Friscic, C D Sadik, T Harrer, J Köhl, G Schett, L Munoz, A Fähnrich, S Murthy, R Grieshaber-Bouyer, M Herrmann, R Bilyy, H R Griffiths, A Mokhir, M H Hoffmann.

  Reactive oxygen species (ROS) generated by NADPH oxidase 2 (NOX2) are essential for antimicrobial defense but also for the resolution of inflammation. NOX2 deficiency, as observed in chronic granulomatous disease (CGD), predisposes to persistent sterile inflammation. Current therapeutic strategies largely rely on nonspecific immunosuppression or require residual NOX2 activity, while systemic ROS-inducing therapies are limited by toxicity. Here, we present a NOX2-independent approach to restore inflammation-resolving ROS signaling using N-alkylaminoferrocene-based prodrugs (pro-NAAFs), which amplify pre-existing ROS rather than generating ROS indiscriminately. Among several candidates, prodrug 1 emerged as the most potent and well-tolerated ROS amplifier. In human neutrophils, prodrug 1 induced strong ROS production and neutrophil extracellular trap (NET) formation. These responses occurred independently of NOX2 and were maintained in CGD-derived neutrophils. Similar NOX2-independent ROS induction and NET formation were observed in immune cells from wild-type and NOX2-dysfunctional Ncf1∗∗ mice. Prodrug 1-induced NETs aggregated into high-density structures (aggNETs) capable of degrading pro-inflammatory mediators in vitro. Prodrug 1 also inhibited neutrophil inflammasome activation. In vivo, subcutaneous administration of prodrug 1 reduced inflammatory mediator levels in air pouches, promoted resolution of chronic arthritis in Ncf1∗∗ mice, and protected from bone destruction. Transcriptomic analyses indicated early suppression of inflammatory pathways and restoration of neutrophil maturation trajectories towards a wild-type-like state. While prodrug 1 increased protein oxidation markers, it shifted systemic oxysterol profiles towards an inflammation-resolving phenotype. These findings identify pro-NAAFs as NOX2-independent ROS amplifiers capable of restoring inflammatory resolution and highlight their therapeutic potential for chronic inflammatory conditions linked to NOX2-dysfunction.

Keywords:  Arthritis; Inflammation; NETosis; NOX2; Prodrugs; ROS

DOI:  https://doi.org/10.1016/j.redox.2026.104302
Sci Adv. 2026 Jul 24. 12(30): eaeb0060

Single-cell chromatin state transitions during epigenetic memory formation.

Taihei Fujimori, Abby R Thurm, Simon Gaudin, Carolina Rios-Martinez, Benjamin R Doughty, Michaela M Hinks, Joydeb Sinha, Derek Le, Antonina Hafner, William J Greenleaf, Alistair N Boettiger, Lacramioara Bintu.

Repressive chromatin modifications compact chromatin and mediate heritable gene silencing, but how structural changes quantitatively relate to epigenetic memory remains unclear. Using targeted recruitment of the KRAB repressor to induce H3K9me3 at a reporter gene, combined with single-molecule 3D chromatin imaging, we show that irreversible silencing is associated with large-scale chromatin compaction across tens of kilobases. In contrast, histone deacetylation produces reversible silencing without such compaction. Despite substantial single-cell heterogeneity, average compaction at the end of silencing quantitatively predicts epigenetic memory weeks after KRAB removal. Here, memory arises not through stable H3K9me3 domains but rather through a dynamic handoff in which H3K9me3 is gradually lost and replaced by DNA methylation. Stochastic simulations recapitulating these dynamics suggest that compaction enhances read-write feedback to promote this transition. Similar compaction is observed at endogenous loci during differentiation and fate commitment, suggesting that spatial organization may be predictive of epigenetic memory in other systems.

DOI: https://doi.org/10.1126/sciadv.aeb0060
Mol Cell. 2026 Jul 21. pii: S1097-2765(26)00465-X. [Epub ahead of print]

Temporal control of macrophage pro-inflammatory phenotype by a biphasic HIF-1α regulatory program.

Gustavo Gastão Davanzo, Guilherme Ribeiro, Douglas Dos-Santos, Marcelo Rodrigues Berçot, Isabella Zaidan, Larissa Menezes Dos Reis, João Victor Virgilio-da-Silva, Bianca Gazieri Castelucci, Paulo Estevão, Wanderson Dourado Souza, Henver S Bruneta, José Luis Fachi, Webster Leonardo Costa, João Nilton Barreto Andrade, Gerson S Profeta, Rodrigo Requião Dias, Natália S Wassano, Lauar de Brito Monteiro, Jessica Aparecida da Silva Pereira, Cristhiane Favero de Aguiar, Monara Kaélle Sérvulo Cruz Angelim, Wilias Greison Santos, Victor Corasolla Carregari, Jonathan Peña, Carlos Alberto de Carvalho Fraga, Marcelo A Mori, Silvio Roberto Consonni, Daniel Martins-de-Souza, Marco Aurélio Ramirez Vinolo, Helder Nakaya, Peter J Murray, Afshin Beheshti, Larissa Dias Cunha, Pedro M Moraes-Vieira.

  Hypoxia-inducible factor 1α (HIF-1α) broadly orchestrates metabolic reprogramming in inflammatory macrophages. However, how HIF-1α shapes the earliest events following activation of pattern recognition receptors and triggers inflammatory responses remain unclear. We found that HIF-1α is functionally active shortly after macrophage inflammatory stimulation via a Rubicon (RUBCN)-NADPH oxidase (NOX2) reactive oxygen species (ROS) circuit, driving glycolysis, cytokine production, and bacterial killing before maximal protein accumulation. Early HIF-1α stabilization primes inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production, which subsequently suppresses electron transport chain function and induces mitochondrial dysfunction independently of RUBCN and NOX2. These findings elucidate a temporally coordinated HIF-1α pathway that integrates RUBCN-NOX2 redox signaling to control macrophage inflammation, metabolic adaptation, and antimicrobial defense.

Keywords:  HIF-1α; NADPH oxidase 2; NOX2; glycolisis; hypoxia-inducible factor 1-alpha; macrophage metabolic reprogramming; mitochondria; rubicon

DOI:  https://doi.org/10.1016/j.molcel.2026.07.001