bims-traimu 2026-08-30 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–08–30
seventeen papers selected by
Yantong Wan, Southern Medical University

Trained Immunity in Host Defense: Mechanisms, Pathogen Interactions, and Therapeutic Potential.
Immunopharmacological reprogramming of innate immune memory in Alzheimer's disease: From microglial priming to therapeutic resilience.
Trained immunity in gout: epigenetic and metabolic reprogramming of innate immune memory.
ACC1 inhibition enhances BCG-induced trained immunity by reprogramming Acetyl-CoA metabolism.
Stress-induced trained immunity-A key mechanism linking psychosocial stress, atherosclerosis, and cardiovascular disease.
Trained Immunity Attenuates Bleomycin-Induced Pulmonary Fibrosis by Promoting AMPK-Mediated Autophagy in Alveolar Macrophages.
LPS and β-Glucan Induce Differential Memory-like Inflammatory Responses with Enhanced Reactivity in Neonatal Neutrophils Compared to Adults.
Altered bone marrow niche forms central innate immune memory driving cardiac dysfunction.
Mucosal BCG Vaccination and Immune Layering: Route-Dependent Programming of Immunity at the Respiratory Interface.
Metabolic Memory in Cardiovascular Disease: Encoding, Propagation, and Therapeutic Targeting.
Macrophage PARP7 Alleviates Septic Cardiomyopathy by Interacting With TBK1 and Suppressing TBK1-Driven Inflammatory Response.
The cost of persistent alarm: temporal transcriptional reprogramming of macrophages from acute activation to chronic immune suppression by day 11.
Targeting the NR1D1-IGF2BP2-V-ATPase Axis With Hybrid Nanovesicles Restores Macrophage Rhythms to Reverse Sepsis-Induced Immunosuppression.
Synergistic interaction between the macrophage polarizing signals IL-4 and IFNγ is controlled by the STAT6/STAT1/IRF1 axis.
A single-cell transcriptomic atlas reveals the immune panorama of neonatal sepsis.
Temporal analyses of immune responses in sepsis reveal asynchrony between clinical stage of illness and immune states.
Type I IFN-induced IFN-γ instructs monocyte-mediated systemic bacterial protection during type 2 intestinal helminth infection.

Pathogens. 2026 Aug 10. pii: 834. [Epub ahead of print]15(8):

Trained Immunity in Host Defense: Mechanisms, Pathogen Interactions, and Therapeutic Potential.

Farha Siddiqui, Anindita Datta, Shivani Choubey, Subhasish Bhadra, Arif Siddiqui, Kalpana Sadawarte.

  Trained immunity refers to the functional reprogramming of innate immune cells-such as monocytes, macrophages, and natural killer cells-those results in a modulated, and often heightened, response to secondary stimuli. This phenomenon challenges the traditional view that immunological memory is restricted to the adaptive immune system and has emerged as a concept linking host defense, vaccination, and inflammatory disease. This review synthesizes current evidence on the molecular basis of trained immunity, including chromatin remodeling, histone modifications, and metabolic rewiring, and examines how bacteria, viruses, and fungi induce, evade, or exploit these programs. The dual contribution of trained immunity to protective host defense and to immunopathology is discussed, along with its implications for vaccine design-including heterologous protection reported after BCG vaccination-and its potential as a therapeutic target in infectious and inflammatory disease. Key gaps, particularly the duration and reversibility of the trained state, the distinction between trained immunity and related processes such as innate tolerance, and the need for validated biomarkers, are highlighted, together with priorities for future translational research.

Keywords:  epigenetic reprogramming; heterologous immunity; innate immune memory

DOI:  https://doi.org/10.3390/pathogens15080834
Biochem Pharmacol. 2026 Aug 22. pii: S0006-2952(26)00720-3. [Epub ahead of print]254(Pt 1): 118381

Immunopharmacological reprogramming of innate immune memory in Alzheimer's disease: From microglial priming to therapeutic resilience.

Ahmed M Abdelaziz, Reem M Eladawy.

  Alzheimer's disease (AD) is increasingly recognized as a disorder driven by dysregulated innate immunity rather than merely amyloid‑β accumulation. Microglia, the brain's resident innate immune cells, acquire long‑term functional memory, a process known as trained immunity or innate immune memory, through epigenetic and metabolic reprogramming. In AD, chronic exposure to amyloid‑β and tau aggregates locks microglia into a maladaptive primed state characterized by altered histone modifications (H3K4me3, H3K27ac), sustained glycolysis via the HIF‑1α/mTOR axis, and impaired phagocytic function, perpetuating neuroinflammation and neurodegeneration. This review critically synthesizes recent advances that define the molecular architecture of microglial immune memory, including epigenetic rewiring, immunometabolic shifts, and intercellular crosstalk with astrocytes and the gut microbiome. We evaluate the emerging immunopharmacological toolbox designed to reverse maladaptive priming and restore neuroprotective resilience, focusing on small‑molecule NLRP3 inflammasome inhibitors (HT‑6184, DFV890, BGE‑102), TREM2 agonists (VG‑3927, MNA‑001), metabolic modulators (metformin, rapamycin), trained immunity‑based vaccination (BCG), specialized pro‑resolving mediators (maresin 1, resolvin D1, lipoxin A4), and senolytics. Clinical‑stage agents and their mechanisms of action are highlighted. We argue that the next generation of AD therapeutics must move beyond target suppression toward the functional reprogramming of brain innate immunity, and we propose a biomarker-guided, patient-stratified framework that integrates multimodal immunopharmacology, combining NLRP3 inhibition, TREM2 agonism, metabolic reprogramming, and resolution pharmacology to restore immune homeostasis. Harnessing the plasticity of innate immune memory offers a transformative paradigm for disease‑modifying therapy in AD.

Keywords:  Alzheimer’s disease; BCG vaccine; Epigeneticre programming; Immunometabolism; Microglial priming; NLRP3inflammasome; Resolution pharmacology; TREM2; Trained immunity

DOI:  https://doi.org/10.1016/j.bcp.2026.118381
Front Immunol. 2026 ;17 1914001

Trained immunity in gout: epigenetic and metabolic reprogramming of innate immune memory.

Xin Chen, Yongtong Huan, Raobin Xu, Jiayi Fan, Jieru Han.

  Gout is a chronic inflammatory arthritis driven by monosodium urate (MSU) crystal deposition. Its global prevalence is rising steadily. Only a minority of hyperuricemic individuals develop gout, and flares often recur despite controlled serum urate, pointing to mechanisms beyond simple crystal-induced inflammation. This review synthesizes evidence that trained immunity-the persistent epigenetic and metabolic reprogramming of innate immune cells-underpins these paradoxes. MSU crystals and soluble urate act as dual inducers: crystals trigger acute flares via NOD-, LRR- and pyrin domain-containing protein 3(NLRP3) and also establish long-lived myeloid memory through c-Jun N-terminal kinase (JNK)-c-Jun proto-oncogene (JUN) and mechanistic target of rapamycin (mTOR)-hypoxia-inducible factor 1-alpha (HIF-1α) axes, while soluble urate primes cells via DNA hypomethylation and histone modifications. We detail the molecular architecture of trained immunity in gout, including central [hematopoietic stem and progenitor cells (HSPC)] and peripheral training, metabolic rewiring (glycolysis, succinate), epigenetic marks (H3K4me3, H3K27ac, DNA methylation), and non-coding RNA regulation. We discuss how trained macrophages and Th17 cells form a self-amplifying loop, and how systemic trained immunity links gout to cardiovascular disease, chronic kidney disease, and metabolic syndrome, with clonal haematopoiesis of indeterminate potential (CHIP) as an age-related amplifier. Finally, we evaluate therapeutic strategies targeting epigenetic enzymes, metabolic nodes, and interleukin-1 beta (IL-1β), and highlight biomarkers and trial design needed to translate trained immunity modulation into clinical practice.

Keywords:  NLRP3 inflammasome; clonal haematopoiesis; epigenetics; gout; inflammation; metabolic reprogramming; monosodium urate; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2026.1914001
Mol Ther. 2026 Aug 25. pii: S1525-0016(26)00714-8. [Epub ahead of print]

ACC1 inhibition enhances BCG-induced trained immunity by reprogramming Acetyl-CoA metabolism.

Ilayda Baydemir, Fabian Nikolka, Özlem Bulut, Anaísa V Ferreira, Gizem Kilic, Büsra Geckin, Robbin Kramer, Jorge Cuenca-Escalona, Evelien Floor, Marisol Báez-Magaña, Vasiliki Matzaraki, Jeroen Deckers, Tom Anbergen, Yuri van Elsas, Thijs Beldman, Simone Jcfm Moorlag, L Charlotte J de Bree, Victoria Spanou, Theano Andriopoulou, Yang Li, Evangelia Karagianni, Boris Novakovic, Yahya Sohrabi, Leo A B Joosten, Karsten Hiller, Jorge Domínguez-Andrés.

Trained immunity enhances long-term innate immune responsiveness through metabolic and epigenetic rewiring. Using BCG as a model, we demonstrate that inhibition of acetyl-CoA carboxylase 1 (ACC1) enhances BCG-induced trained immunity by increasing intracellular acetyl-CoA (ACoA) availability. This shift redirects ACoA from lipid biosynthesis towards enhanced tricarboxylic acid (TCA) cycle flux and histone acetylation, reinforcing metabolic and epigenetic programs that sustain trained immunity. ACC1 inhibitors amplify cytokine production, mitochondrial respiration, and glutamine metabolism in monocytes, with heightened histone H3K27 acetylation and reduced H3K9 methylation at pro-inflammatory loci. In vivo, ACC1 inhibition amplified BCG-driven myelopoiesis, increasing granulocyte-macrophage progenitors and systemic cytokine responses. Notably, genetic variation in ACoA metabolism genes influenced trained immunity responses in BCG-vaccinated individuals. These findings highlight ACC1 as a metabolic checkpoint linking cellular metabolism to innate immune memory. Targeting ACoA metabolism may represent a promising strategy to optimize vaccine efficacy and enhance broad-spectrum protection against infections.

DOI: https://doi.org/10.1016/j.ymthe.2026.08.033
FEBS Lett. 2026 Aug 29.

Stress-induced trained immunity-A key mechanism linking psychosocial stress, atherosclerosis, and cardiovascular disease.

Dineke C W Touw, Saloua El Messaoudi, Willem J M Mulder, Mihai G Netea, George M Slavich, Niels P Riksen.

  Although chronic psychosocial stress is a well-established independent risk factor for cardiovascular disease (CVD), the underlying mechanisms linking stress to CVD remain incompletely understood. Here, we review clinical and preclinical research documenting how stress can activate innate immune cells. Based on these findings, we propose that trained innate immunity is one possible mechanism responsible for the lasting effects of stress on the innate immune system, and hence contributes to the association between stress and CVD. Trained immunity is defined as a persistent hyperinflammatory phenotype in innate immune cells, mediated by metabolic and epigenetic reprogramming of the bone marrow myeloid progenitor cells. As we describe herein, accumulating experimental evidence shows that chronic psychosocial stress can induce a maladaptive trained immunity program that accelerates atherosclerosis. By advancing our understanding of stress-induced trained immunity, we will move one step closer to designing new therapeutic, behavioral, and lifestyle strategies to counter maladaptive immune activation and reduce risk for CVD, one of the greatest causes of morbidity and mortality worldwide.

Keywords:  atherosclerosis; cardiovascular disease; inflammation; psychosocial stress; trained immunity

DOI:  https://doi.org/10.1002/1873-3468.70447
Biology (Basel). 2026 Aug 11. pii: 1366. [Epub ahead of print]15(16):

Trained Immunity Attenuates Bleomycin-Induced Pulmonary Fibrosis by Promoting AMPK-Mediated Autophagy in Alveolar Macrophages.

Xinru Wang, Xinya Guo, Huiwen Meng, Zhiheng Sun.

  Trained immunity (TI) represents a form of immune memory in innate immune cells, driven by sustained epigenetic and metabolic reprogramming that potentiates innate immune responses. Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by persistent alveolar injury and pathological tissue remodeling. Given the central role of macrophages in IPF pathogenesis, we hypothesized that inducing TI could functionally reprogram these cells and attenuate fibrosis. In a murine model of pulmonary fibrosis induced by bleomycin, prior induction of TI via β-glucan enhanced autophagic activity in macrophages and reduced pathological collagen deposition. This trained response restricted bleomycin-triggered mitochondrial DNA release and suppressed the mitochondrial apoptosis pathway, thereby promoting macrophage survival. The protective effects were diminished by administration of the AMPK inhibitor Compound C. Our findings indicate that TI promotes mitophagy correlating with the AMPK-ULK1 signaling axis, thereby reducing alveolar macrophage apoptosis and uncovering a potential therapeutic strategy for pulmonary fibrosis.

Keywords:  AMPK; alveolar macrophages; autophagy; mitochondria; pulmonary fibrosis; trained immunity

DOI:  https://doi.org/10.3390/biology15161366
Int J Mol Sci. 2026 Aug 14. pii: 7268. [Epub ahead of print]27(16):

LPS and β-Glucan Induce Differential Memory-like Inflammatory Responses with Enhanced Reactivity in Neonatal Neutrophils Compared to Adults.

Lisa Zagler, Laura Snaidr, Natascha Köstlin-Gille, Heidi Hildenbrand, Nadja Kliegel, David L Williams, Ricarda Will, Stefanie Dietz-Ziegler, Cahit Birdir, Christian Gille, Trim Lajqi.

  Neutrophils are key effectors of innate immunity. Although traditionally regarded as short-lived effector cells, recent evidence suggests they can undergo functional reprogramming after microbial stimulation, leading to trained immunity. We investigated whether lipopolysaccharide (LPS) or Candida albicans β-glucan induces memory-like inflammatory responses in adult peripheral and neonatal cord blood neutrophils. We used complementary molecular and functional approaches to characterize neutrophil responses following in vitro priming with LPS or β-glucan and subsequent LPS restimulation. Cytokine secretion, reactive oxygen species (ROS) production, glycolytic activity (via lactate production and glycolytic enzyme expression), and ERK1/2 and NF-κB signaling pathway activation were assessed. Priming with LPS or β-glucan enhanced neutrophil responsiveness to secondary stimulation, resulting in increased secretion of IL-1β, IL-6, IL-8, CXCL1, and CCL2, together with elevated ROS production. These effects were consistently more pronounced in neonatal than in adult neutrophils. Memory-like neutrophils also exhibited metabolic reprogramming, associated by increased hexokinase-2 and phosphofructokinase-1 mRNA expression, elevated lactate production, and enhanced ERK1/2 and NF-κB activation. Human neutrophils, particularly neonatal cells, develop memory-like characteristics following LPS or β-glucan priming, highlighting their functional and metabolic plasticity and suggesting a role for neutrophil training in early-life immune adaptation.

Keywords:  adult; inflammation; memory-like; metabolism; neonates; neutrophils; signaling

DOI:  https://doi.org/10.3390/ijms27167268
Nat Commun. 2026 08 26. pii: 8261. [Epub ahead of print]17(1):

Altered bone marrow niche forms central innate immune memory driving cardiac dysfunction.

Kohsaku Goto, Yukiteru Nakayama, Junichi Sugita, Tsukasa Oshima, Kunihito Kani, Atsushi Kobayashi, Naoto Setoguchi, Yuxiang Liu, Yiyi Yang, Jiaxin Ku, Ryoko Uchida, Eriko Hasumi, Takashi Nagasawa, Issei Komuro, Norihiko Takeda, Ichiro Manabe, Katsuhito Fujiu.

We previously showed that heart failure induces innate immune memory in hematopoietic stem and progenitor cells, which contributes to recurrence of heart failure and impaired stress responses in multiple organs. While the bone marrow microenvironment maintains blood cell formation, its role in this memory remains poorly understood. Here we show that bone marrow mesenchymal stromal cells expressing the leptin receptor influence hematopoietic stem and progenitor cells to promote cardiac pathology. Transplanting these stromal cells from mice with heart failure together with healthy hematopoietic cells caused inflammatory macrophages to accumulate in the heart and worsened cardiac remodeling. Mechanistically, heart failure reduced a stromal subpopulation producing heparin-binding epidermal growth factor and suppressed growth factor signaling in hematopoietic cells. Heart failure also activated a fat-forming program in stromal cells. Notably, an equivalent stromal subpopulation exists in human bone marrow, and heart failure was associated with increased bone marrow fat in humans, identifying the bone marrow microenvironment as a regulator of innate immune memory.

DOI: https://doi.org/10.1038/s41467-026-76178-z
Vaccines (Basel). 2026 Jul 31. pii: 667. [Epub ahead of print]14(8):

Mucosal BCG Vaccination and Immune Layering: Route-Dependent Programming of Immunity at the Respiratory Interface.

Yukihiro Shibuya, Miyu Sakai, Hideyasu Kiyohara.

  Mycobacterium bovis Bacille Calmette-Guérin (BCG), the only licensed vaccine against tuberculosis, provides inconsistent protection against pulmonary tuberculosis, reflecting an incomplete understanding of how vaccine-induced immunity is organized within tissues. Emerging evidence indicates that the route of vaccination is not merely a technical variable but a critical determinant of immune programming. Whereas parenteral BCG primarily elicits systemic immune responses, mucosal delivery reprograms immunity at the respiratory interface by promoting localized trained innate immunity, tissue-resident memory T (TRM) cells, and early containment of infection. In this review, we propose an integrated framework of "immune layering," in which protection emerges through the coordinated interactions of epithelial regulation, trained innate immunity, tissue-resident adaptive memory, regulatory homeostasis, and systemic immune support across spatial and temporal scales. Within this framework, trained innate immunity serves as an initial conditioning layer that shapes subsequent adaptive differentiation, whereas epithelial- and microbiota-associated regulatory networks establish the tissue context in which immune responses are initiated, organized, and maintained. Importantly, effective mucosal immunity depends on a dynamically regulated equilibrium rather than maximal immune activation. The dissociation between enhanced early pulmonary immune responses and limited long-term protection underscores the influence of tissue-specific regulatory constraints and environmental context on vaccine efficacy. This framework redefines correlates of protection by identifying the vaccination route and tissue-level immune organization as fundamental determinants of protective immunity, thereby providing a conceptual foundation for the rational development of next-generation mucosal tuberculosis vaccines.

Keywords:  Bacille Calmette–Guérin (BCG); immune layering; mucosal immunity; tissue-resident memory T cells; trained immunity; tuberculosis; vaccination route

DOI:  https://doi.org/10.3390/vaccines14080667
Adv Sci (Weinh). 2026 Aug 27. e77260

Metabolic Memory in Cardiovascular Disease: Encoding, Propagation, and Therapeutic Targeting.

Cheng Cheng, Minghui Tang, Zhaobo Zhang, Ruoyi Qu, Jianfei Pei, Tian Liu, Siyao Qu, Shilong You, Shenshen Cui, Wenke Wang, Rui Zhao, Yingxian Sun, Naijin Zhang.

  Cardiovascular risk in metabolic disease persists long after the initiating metabolic abnormalities are corrected, a phenomenon termed metabolic memory. The DCCT/EDIC cohort is illustrative: early glycemic control produced cardiovascular protection that peaked within a decade and left a lasting legacy. The same strategy applied after prolonged hyperglycemia, however, has not reproduced this benefit. This conceptual Review proposes a framework in which such persistent risk arises from four distinct processes: encoded epigenetic memory, irreversible structural damage, chronic input from dysfunctional organs, and delayed tissue remodeling, each with a different therapeutic logic. Persistence of these encoded marks is established most directly in immune-lineage cells; its extension to cardiomyocytes remains a working hypothesis. Only encoded memory is accessible to chromatin-directed reversal, and only before metabolic stress exhausts the erasure machinery that keeps marks revisable, a time-dependence proposed to explain why early intervention succeeds where late intervention fails. Clinical efficacy therefore may depend on engaging the substrate maintaining pathology rather than normalizing a surrogate biomarker, a substrate-alignment principle consistent with the divergent outcomes of recent cardiometabolic trials. We apply the framework to atherosclerosis, heart failure, and diabetic cardiomyopathy, grade its claims by a three-tier evidence classification, and specify testable predictions that could refute it.

Keywords:  atherosclerosis; diabetic cardiomyopathy; epigenetic regulation; heart failure; metabolic memory; trained immunity

DOI:  https://doi.org/10.1002/advs.77260
Adv Sci (Weinh). 2026 Aug 24. e77404

Macrophage PARP7 Alleviates Septic Cardiomyopathy by Interacting With TBK1 and Suppressing TBK1-Driven Inflammatory Response.

Jibo Han, Lintao Wang, Xin Zhong, Shenggang Zhao, Huihui Xie, Xue Han, Liming Lin, Yiting Lyu, Ke Xu, Jiajun Xu, Xiaowen Shi.

  Septic cardiomyopathy is a life-threatening complication of sepsis, and an uncontrolled inflammatory response represents a key pathogenic mechanism. PARP7 negatively regulates the IFN-I signaling pathway through a mono-ADP-ribosylation-dependent interaction with TBK1. Here, through comprehensive analysis of the expression profile of the PARP family in LPS-treated myocardial tissues, we propose that PARP7 may be associated with septic cardiomyopathy. Then, we demonstrate that PARP7 deficiency exacerbates LPS-induced septic cardiomyopathy in vivo. Integrated single-nucleus and single-cell RNA sequencing analyses demonstrate that PARP7 is predominantly upregulated in macrophages in the hearts of LPS-treated mice. Using an AAV9-based delivery system, we further validated the cardioprotective role of macrophage-specific PARP7 in murine models of sepsis induced by either LPS or CLP. Mechanistically, PARP7 interacts with TBK1 to mediate its ADP-ribosylation, thereby suppressing the TBK1-driven inflammatory response in macrophages. The snRNA-seq and cytokine array data collectively support a critical role for PARP7 as a molecular "brake" that constrains excessive macrophage inflammation. In conclusion, this work identifies a macrophage-specific PARP7-TBK1 regulatory axis in septic cardiomyopathy and highlights the therapeutic potential of macrophage-specific PARP7 overexpression.

Keywords:  PARP7; TBK1; macrophage; mono‐ADP‐ribosylation; septic cardiomyopathy

DOI:  https://doi.org/10.1002/advs.77404
Front Immunol. 2026 ;17 1729108

The cost of persistent alarm: temporal transcriptional reprogramming of macrophages from acute activation to chronic immune suppression by day 11.

Elizabeth A Mazzio, Andrew S Barnes, Ramesh B Badisa, Selina F Darling-Reed, Karam F A Soliman.

   Introduction: Chronic inflammation has long been associated with cancer initiation, yet the mechanisms linking sustained immune activation to an immune-permissive tumor microenvironment remain incompletely defined. Prevailing explanations such as immune exhaustion (IEX) or free radical mediated tissue damage, fail to account for the active state of immune tolerance, a process driven by potent negative feedback loops that systematically suppress host effector responses.
Methods: To address this gap, we developed an in vitro model of macrophage tolerance driven by sustained Toll-like receptor 4 (TLR4) activation using microbial-associated molecular patterns (MAMPs). This system captures the full kinetic progression of the immune response, tracking macrophages from a resting baseline, through acute activation at 24 hours, to a chronic tolerant endpoint at 7-11 days. Methodologically, cells were maintained under a continuous media exchange (+/- E. coli O111:B4 LPS) featuring high glucose and an elevated volume-to-cell ratio. This setup effectively eliminates autocrine interference and toxic byproducts, successfully isolating the direct consequences of sustained TLR4 signaling across extended durations.
Results: Whole-transcriptome sequencing, validated by RT-PCR and select protein immunoblots, revealed that both "exhaustion" and "tolerance" are mischaracterized. Rather than a passive exhaustion state or a simple trajectory of diminishing returns, the resting-acute-chronic continuum drives a potent, active negative-feedback mechanism across an eight-phase bidirectional trajectory. By days 7-11, macrophages shifted to a TAM-like signature, overexpressing immune checkpoints (PD-L1/MSN, TIM-3, SPP1, CD73, CD44, LILRs) and regulatory suppressive networks (SOCS/JAK/STAT, IL-10, CCL2/7/12, CXCL2), while downregulating classical (H2-D1/K1) and non-classical (H2-Q/T) MHC-I antigen-presenting genes. These alterations coincided with the profound loss of interferon-stimulated genes (ISGs) including the IFIT family, Ly6e, Irf7, Rsad2/Viperin, and the Oas gene family, fundamentally crippling the machinery required for antiviral and antitumor immune surveillance. Moreover, this chronic stage drove the upregulation of degradative proteases (cathepsins, Adam8, S100a8, Klk9, carboxypeptidase D), integrins/adhesion molecules (Itga5, Marcks, Msr1/CD204, Alcam), iron-storage transcripts, lipid translocases (Cd36), and fatty acid-binding proteins. Concurrently, macrophages upregulated Nos2/Cox2 alongside the metabolic collapse of mitochondrial OXPHOS genes and Acod1 (itaconate). Uniquely, this negative feedback loop coincided with a sustained, massive surge in a cluster of poorly characterized small proline-rich proteins (SPRRs), specifically Sprr2b, 2e, 2d, 2f, 2g, 2h, 2i, 2j, and 2k.
Discussion: Overall, these results indicate that chronic inflammatory signaling can ultimately trigger a profound coordinated negative-feedback program consistent with a reduced immune recognition and defense pathway signatures. Ultimately, this study provides a reproducible in vitro macrophage model to investigate immune suppression. It offers deeper insights into how chronic inflammation impairs host defenses against viral and tumor cells.

Keywords:  IEX; cancer; immune therapies; macrophage; microbes; tolerance

DOI:  https://doi.org/10.3389/fimmu.2026.1729108
Adv Sci (Weinh). 2026 Aug 24. e77366

Targeting the NR1D1-IGF2BP2-V-ATPase Axis With Hybrid Nanovesicles Restores Macrophage Rhythms to Reverse Sepsis-Induced Immunosuppression.

Lang Chen, Wenyi Lin, Lang Jiang, Xuehui Gao, Chenyan Yu, Jili Han, Zhenping Liu, Xuefeng Li, Mei He, Chang Li, Qilan Li, Chaoying Song, Jiqian Xu, You Shang.

  Patients with sepsis exhibit circadian disruption and persistent immunosuppression. However, the molecular mechanisms linking them remain unclear. Integration of multi-cohort transcriptomic and single-cell datasets shows that circadian gene dysregulation in patients with sepsis and septic mice correlates with disease severity and immunosuppressive states, with monocytes/macrophages emerging as a principal affected population. Sustained endotoxin stimulation elevates the core clock repressor NR1D1 in macrophages, which occupies the Igf2bp2 promoter and suppresses its transcription. Loss of IGF2BP2 destabilizes the V-ATPase subunit transcripts Atp6v1b2 and Atp6v0c through an m6A-dependent mechanism, disrupting phagolysosomal acidification rhythms and pathogen clearance. siRNA-mediated NR1D1 knockdown restores IGF2BP2 expression, circadian oscillations, and phagolysosomal function during the development of endotoxin tolerance. To achieve therapeutic delivery, we engineer hybrid membrane nanovesicles (siNR1D1@HM-LNP) that reverse circadian and immune dysregulation in septic mice, enhance bacterial clearance, and markedly improve survival. These findings establish an NR1D1-mediated circadian-immune coupling mechanism and provide a therapeutic strategy for targeting sepsis-induced immunosuppression.

Keywords:  circadian rhythm; drug delivery; nanoparticle; sepsis; siRNA

DOI:  https://doi.org/10.1002/advs.77366
Nucleic Acids Res. 2026 Aug 24. pii: gkag825. [Epub ahead of print]54(16):

Synergistic interaction between the macrophage polarizing signals IL-4 and IFNγ is controlled by the STAT6/STAT1/IRF1 axis.

Zsófia Varga, Anna Poscher, Eszter Anna Váradi, Gyöngyi Cinege, Antal Izsán, Edina Erdős, Bernadett Benyhe-Kis, Anna Zsuzsanna Tihanyi, Petros Tzerpos, Krisztián Bene, László Halász, Nikolett Gémes, Patrícia Neuperger, Márta Tóth, Ede Migh, Szilárd Póliska, Gábor J Szebeni, Jolán E Walter, Bence Dániel, Bálint Csörgő, László Nagy, Zsolt Czimmerer.

IFNγ and IL-4, the canonical Th1 and Th2 cytokines, typically induce opposing macrophage polarization. Beyond their frequent coexistence and mutual antagonism in pathological settings, a synergistic crosstalk may also exist and remains to be defined. Through integrated transcriptomic, epigenomic, and CRISPR-based analyses, we identify that co-exposure to IL-4 and IFNγ results in an intermediate macrophage polarization state in murine macrophages, associated with a cohort of synergistically activated genes. We show that this synergistic activation is mediated by co-binding of STAT6 and STAT1 at regulatory regions marked with pronounced H3K27Ac accumulation and is dependent on the BRD4 cofactor. Deletion of either STAT factor or disruption of their binding motifs abolishes the synergistic transcriptional response. Our data support a model in which chromatin openness induced by one cytokine facilitates binding of the opposing cytokine-activated STAT transcription factor (TF), contributing to synergistic gene activation. We further show that IRF1, an IFNγ-induced TF whose expression persists in the presence of IL-4, is indispensable for a substantial subset of this program. Importantly, single-cell RNA sequencing of the PyMT murine breast cancer model reveals an in vivo tumor-associated macrophage subset showing STAT1 and STAT6 activation and is enriched for the synergistic gene signature.

DOI: https://doi.org/10.1093/nar/gkag825
Cell Rep. 2026 Aug 24. pii: S2211-1247(26)00956-3. [Epub ahead of print]45(9): 117878

A single-cell transcriptomic atlas reveals the immune panorama of neonatal sepsis.

Jie Wang, Ying Chen, Peicen Zou, Yue Du, Ying Li, Li Zhang, Juan Zhou, Linglong Wan, Yifei Xu, Yi Wang, Yajuan Wang, Lihui Meng.

  Neonatal sepsis remains a leading cause of infant mortality, yet mechanisms driving concurrent hyperinflammation and immunosuppression remain unclear. Here, we perform single-cell RNA sequencing on 26 blood samples from 18 neonates, spanning acute sepsis, convalescence, and healthy controls. We identify 57 cell subtypes, revealing acute lymphoid depletion and myeloid expansion. S100A8+ myeloid-derived suppressor cell-like (MDSC-like) cells represent a putative cytokine-storm source, potentially amplified by a feedforward S100-TLR4-MYD88 circuit. Innate-like lymphocytes fail to expand, succumbing to apoptosis and exhaustion despite heightened cytotoxicity. CD4+ T cells display mitochondrial dysfunction, while regulatory T cells acquire a hyper-suppressive phenotype via the LGALS9-HAVCR2 axis. CD8+ T cells undergo interferon-driven, innate-like reprogramming before lapsing into exhaustion, and B cells shift toward stress-adaptive, tolerogenic states. Together, our atlas defines a dual pathology in which MDSC-like cell-driven cytokine storm coexists with multi-lineage immunoparalysis, nominating the S100-TLR4 axis and mitochondrial dysregulation as potential therapeutic targets.

Keywords:  CP: immunology; T cell exhaustion; cytokine storm; neonatal sepsis; peripheral immune response; scRNA-seq

DOI:  https://doi.org/10.1016/j.celrep.2026.117878
Immunity. 2026 Aug 28. pii: S1074-7613(26)00325-0. [Epub ahead of print]

Temporal analyses of immune responses in sepsis reveal asynchrony between clinical stage of illness and immune states.

Matthew Fish, Jennifer Rynne, Emma Timms, Aislinn Jennings, Carolynn Lam, Gill Arbane, Neus Novellas, Sara Campos, Barney Sanderson, Paolo Bosco, Gianluca Lucchese, Richard Ellis, Cynthia Bishop, Katrina Todd, Yasmeen Ghnewa, Mervyn Singer, Chad Swanson, Manu Shankar-Hari.

  Deeper understanding of the temporal immune response architecture in sepsis may enable effective therapeutic interventions. Here, we investigated longitudinal immune response programs in critically ill patients with sepsis, as compared with elective cardiac surgery patients. Although transcriptomic profiles obtained at four clinical time points between admission and recovery or death showed substantial overlap, pseudotime analysis revealed a trajectory comprising three sepsis temporal immune states (STImS1-3). Weighted gene co-expression network analysis and immunophenotypic and cytokine profiles identified distinct programs associated with each STImS, and corresponding hub genes mapped to putative immunomodulatory targets, including interleukin 6 blockade, iron chelation, and anthracyclines. STImS1 was characterized by the strongest innate immune responses, elevated resistance programs, variable disease tolerance programs, and enrichment of low-resilience features, including mortality-associated signatures. In contrast, STImS3 was enriched for adaptive immune responses. Thus, clinical time and immune response trajectory are partially decoupled in sepsis, illustrating the need to align therapeutic intervention with the temporal immune state in sepsis.

Keywords:  cytokines; immunology; immunophenotyping; leukocyte subsets; precision medicine; sepsis; systems biology; trajectory models; transcriptomics

DOI:  https://doi.org/10.1016/j.immuni.2026.08.003
Sci Immunol. 2026 Aug 28. 11(122): eaeh4719

Type I IFN-induced IFN-γ instructs monocyte-mediated systemic bacterial protection during type 2 intestinal helminth infection.

Kelly Wemyss, Lauren M Webb, Hayley M Bridgeman, Ian E Prise, Rufus H Daw, Verena Kästele, Tovah N Shaw, Sabrina Tamburrano, Seona Thompson, Elia D Tait Wojno, Pedro H Papotto, Richard K Grencis, Andrew S MacDonald, Jennifer S Cavet, Joanne E Konkel, Kathryn J Else, John R Grainger.

Alterations to monocyte output and function occur during infections driving T helper 1 (TH1)-type inflammation. The degree to which monocytes respond to infections initiating alternative types of responses is poorly understood. Here, we describe a distinct state of the monocyte compartment associated with type 2-polarizing intestinal helminths. Unexpectedly, the adapted monocyte state in a type 2 setting was associated with acquisition of an interferon (IFN) signature. This IFN-induced state provided helminth-infected animals with systemic protection against secondary bacterial infection and allowed for the development of effective type 2 immunity. This pathway of monocyte education was distinct from that in TH1 settings and involved an endogenous bacteria-mediated induction of type I IFN that led to adaptive lymphocyte-dependent IFN-γ priming of monocytes. These findings reveal an IFN-driven mechanism of monocyte education that enables the host to be simultaneously protected against type 2 infections at barrier sites and type 1 infections in the circulation.

DOI: https://doi.org/10.1126/sciimmunol.aeh4719