bims-traimu 2026-07-12 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–07–12
ten papers selected by
Yantong Wan, Southern Medical University

Metabolic and epigenetic regulation of microglia memory in neurological disorders.
The dual legacy of BCG: a century of tuberculosis prevention and the evolving pursuit of trained immunity-based therapies.
Environmental influences on macrophage epigenetics and trained immunity: a review.
Editorial: Community series in new insights into innate immune cell-based immunotherapies in cancer, volume II.
Metabolic-inflammatory memory: the common pathological basis and therapeutic targets of metabolic syndrome.
DLL4+ Neutrophils Induce Alveolar Macrophages to Cause ADAM-17-mediated Endothelial Barrier Disruption and the Increase of ICAM1hiCXCR1lo Neutrophils in Sepsis.
Chronic intermittent hypoxia sustains the low-grade inflammatory memory of monocytes via activation of myelopoiesis.
RPS20 phosphorylation acts as a molecular switch to integrate inflammatory and oxidative stress signals in sepsis.
Human Alu loci gain enhancer-type epigenetic modifications in monocytes during response to bacterial LPS.
Endurance Exercise Elicits a Hepatic Memory Associated with Improved Metabolic Function and Protein Secretion.

J Leukoc Biol. 2026 Jul 03. pii: qiag085. [Epub ahead of print]118(7):

Metabolic and epigenetic regulation of microglia memory in neurological disorders.

Xiaoya Wang, Yunpeng Jia, Xinyi Yan, Youwei Wang.

  As tissue-resident innate immune cells of the central nervous system, microglia are capable of acquiring innate immune memory-a persistent state of functional reprogramming triggered by prior stimuli. This memory typically manifests as 3 distinct phenotypes: trained immunity, immune tolerance, and immune exhaustion. In this review, we synthesize current knowledge on the metabolic and epigenetic mechanisms that govern these 3 forms of microglial innate immune memory. We further summarize and discuss how each phenotype is induced in microglia and its respective pathophysiological roles in neurological disorders. Owing to their slow turnover and unique tissue-resident characteristics, microglia sustain long-lasting memory states that can profoundly influence the trajectory of neuroinflammation and neurodegeneration. Finally, we highlight the bidirectional effects of microglial immune memory on disease progression, discuss emerging therapeutic strategies aimed at modulating these memory states, and outline key translational challenges that remain to be addressed.

Keywords:  epigenetic reprogramming; innate immune memory; microglia; neurodegenerative diseases; neuroinflammation

DOI:  https://doi.org/10.1093/jleuko/qiag085
Immunotherapy. 2026 Jul 10. 1-15

The dual legacy of BCG: a century of tuberculosis prevention and the evolving pursuit of trained immunity-based therapies.

Nazeer Ahmed, Fatima Jawaid, Muhammad Nabeel.

  The Bacillus Calmette-Guérin (BCG) vaccine, a live-attenuated derivative of Mycobacterium bovis, has long been central to global tuberculosis prevention. Although it protects well against severe childhood TB, its efficacy against adult pulmonary TB is variable. At the same time, epidemiological and clinical observations suggest that BCG may reduce all-cause mortality and protect against infections beyond TB. Randomised trials have reported lower neonatal all-cause mortality and fewer sepsis-related deaths, supporting the idea of broader immunological benefits. These heterologous effects are proposed to be derived from trained immunity, a form of functional reprogramming of innate immune cells driven by epigenetic and metabolic changes. In some settings, BCG may also induce trained tolerance, leading to a more suppressive immune state, based mainly on animal and in vitro evidence. Clinically, intravesical BCG is an established local immunotherapy for non-muscle-invasive bladder cancer, with current evidence and emerging data suggesting that its effects may extend beyond the bladder through systemic immune training. However, repurposing BCG for other cancers, non-oncological autoimmune diseases, and respiratory tract infections remains established in experimental animal models but is represented with mixed efficacy accompanied by inconclusiveness in human trials and mostly in preclinical or early-phase evidence. Major barriers to translation include strain variability, lack of standardised dosing, uncertain durability, and unresolved long-term safety concerns. Future progress will depend on engineered BCG derivatives, improved delivery systems, rational combination therapies, and well-designed controlled clinical trials.Methodology: Literature was identified through searches of PubMed, Google Scholar, and the Cochrane Library, from database inception to 2026, with a primary focus on studies published between 2011 and 2026.

Keywords:  Bacillus Calmette–Guérin; cancer immunotherapy; epigenetic reprogramming; heterologous protection; trained immunity

DOI:  https://doi.org/10.1080/1750743X.2026.2698221
Mol Biol Rep. 2026 Jul 10. pii: 1130. [Epub ahead of print]53(1):

Environmental influences on macrophage epigenetics and trained immunity: a review.

Maryam Emami, Furkan Ayaz.

  Macrophages are central to host immunity and tissue homeostasis, exhibiting remarkable functional plasticity across a continuum of states-ranging from pro-inflammatory (M1-like) to anti-inflammatory and tissue-reparative (M2-like) phenotypes. Environmental exposures can induce persistent epigenetic changes that shape macrophage responses well beyond the acute phase, a phenomenon now recognized as trained immunity. This narrative review synthesizes current knowledge on how diverse components of the exposome-including diet, air pollution, agricultural chemicals, heavy metals, endocrine-disrupting chemicals, per- and polyfluoroalkyl substances (PFAS), alcohol, smoking, the gut microbiome, maternal diet, and psychosocial stress-remodel the macrophage epigenome. We examine the underlying epigenetic mechanisms, namely DNA methylation, histone modifications, and non-coding RNAs, and discuss their impact on macrophage polarization, cytokine production, and trained immunity induction. Special emphasis is placed on the distinction between bona fide trained immunity and transient inflammatory skewing, the limitations of the classical M1/M2 framework, and the identification of "epigenetic vulnerability nodes" at which multiple environmental signals converge on a small set of chromatin-modifying enzymes and transcription factors. We also highlight critical knowledge gaps, including the lack of data for emerging contaminants such as micro- and nanoplastics, the uncertain reversibility of exposure-induced epigenetic marks, and the challenge of demonstrating transgenerational inheritance in humans. By connecting molecular mechanisms with broader public health implications, this review provides a critical framework for understanding environmentally driven immune dysregulation and outlines future research directions, including mixture toxicology, single-cell multi-omics, and the integration of epigenetic endpoints into chemical risk assessment.

Keywords:  Air pollution; DNA methylation; Diet; Epigenetics; Exposome; Histone modification; Macrophage; Microbiome; Stress; Trained immunity

DOI:  https://doi.org/10.1007/s11033-026-12318-4
Front Immunol. 2026 ;17 1898947

Editorial: Community series in new insights into innate immune cell-based immunotherapies in cancer, volume II.

Chiara Porta, Mary Poupot-Marsan, Virginie Lafont.



Keywords:  CAR-NK; Erk5; NK cells; innate immunity; metabolic reprogramming; trained immunity; transcriptomics; tumor microenvironment (TME)

DOI:  https://doi.org/10.3389/fimmu.2026.1898947
Rev Endocr Metab Disord. 2026 Jul 09.

Metabolic-inflammatory memory: the common pathological basis and therapeutic targets of metabolic syndrome.

Xiaoshuo He, Zhanli Guo, Qiu Chen.

  Metabolic syndrome (MetS) is traditionally characterized by a cluster of abnormalities, including obesity, hyperglycemia, dyslipidemia, and hypertension, with clinical management historically centered on the stabilization of these individual parameters. However, the chronic, progressive nature of MetS and the persistent challenge of fully reversing its clinical manifestations indicate that its underlying pathophysiological mechanisms extend far beyond the mere summation of individual risk factors. Recent evidence reveals that the core pathogenesis of MetS involves a complex interplay between "metabolic memory" and "inflammatory memory." Metabolic memory represents the long-term imprint sustained at the cellular level from historical metabolic disturbances, mediated via epigenetic reprograming and mitochondrial dysfunction. Concurrently, inflammatory memory reflects the immune system's "trained immunity" (TI) under metabolic stress, which primes immune cells to maintain a persistent state of low-grade, chronic pro-inflammation. These two pathological processes interact closely through signaling cascades-such as nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), Janus kinase/signal transducer and activator of transcription (JAK-STAT), and Toll-like receptors (TLRs) pathways-thereby translating metabolic danger signals into chronic inflammation and the maladaptive regulation of lipid metabolism, insulin signaling, and vascular function. This cascade amplification mechanism, propagating from localized cellular memory to systemic inflammation, drives progressive end-organ damage in the heart, liver, kidneys, and vasculature, establishing the unifying pathological foundation of MetS and its associated complications. Consequently, clinical intervention strategies for MetS must transition from the superficial management of biochemical indicators toward therapies that specifically target and reverse this deeply ingrained metabolic-inflammatory memory. This review systematically constructs a comprehensive theoretical framework for metabolic-inflammatory memory in MetS and evaluates its clinical translational value, aiming to provide a mechanistic foundation for the development of targeted, curative clinical interventions.

Keywords:  Epigenetics; Inflammatory memory; Metabolic memory; Metabolic syndrome

DOI:  https://doi.org/10.1007/s11154-026-10067-0
J Leukoc Biol. 2026 Jul 10. pii: qiag097. [Epub ahead of print]

DLL4+ Neutrophils Induce Alveolar Macrophages to Cause ADAM-17-mediated Endothelial Barrier Disruption and the Increase of ICAM1hiCXCR1lo Neutrophils in Sepsis.

Hui Jin, Saoirse Holland, Alok Jha, Monowar Aziz, Ping Wang.

  Sepsis remains a leading cause of death. Reverse migrated (RM) neutrophils, characterized as ICAM1hiCXCR1lo, have been recognized as a key driver of systemic inflammation and organ injury in sepsis. We have recently discovered a distinct DLL4+ subset of neutrophils that accumulate in the lungs, contributing to lung injury; however, the underlying mechanism is less understood. In sepsis, ICAM1hiCXCR1lo neutrophils, being hyperactive, were shown to be detrimental. Here, we investigated how DLL4+ neutrophils activate alveolar macrophages (AMs) to cause endothelial cell barrier disruption and promote neutrophil reverse migration. AMs were treated with DLL4+ neutrophils or recombinant mouse DLL4 (rmDLL4), and a disintegrin and metalloprotease (ADAM17) generated by AMs was assessed at both mRNA and protein levels. Conditioned medium was subsequently applied to pulmonary vascular endothelial cells (PVECs); junctional adhesion molecule-C (JAM-C) protein was detected by Western blot assays, and ICAM1hiCXCR1lo neutrophils were detected by flow cytometry. We demonstrate that during sepsis induced by cecal ligation and puncture (CLP), DLL4+ neutrophils interact with AMs via the Notch1 pathway, leading to increase of ADAM17 expression. ADAM17 decreased JAM-C on PVECs, causing endothelial barrier disruption and ICAM1hiCXCR1lo neutrophils generation. Small-molecule inhibitor of ADAM17 effectively preserved pulmonary endothelial barrier integrity, and reduced ICAM1hiCXCR1lo neutrophils accumulation. Importantly, we have developed a novel DLL4-Notch1 inhibitory peptide (NDI) that effectively suppresses ADAM17 expression, restores JAM-C, and reduces ICAM1hiCXCR1lo neutrophils accumulation in sepsis. These findings identify DLL4+ neutrophils as a critical inflammatory mediator that exacerbate systemic inflammation and worsen sepsis, highlight the DLL4-Notch1-ADAM17 axis as a promising therapeutic target.

Keywords:  Alveolar macrophages; DLL4+ neutrophils; DLL4-Notch1-ADAM17 signaling; ICAM1hiCXCR1lo neutrophils; Sepsis

DOI:  https://doi.org/10.1093/jleuko/qiag097
Inflamm Res. 2026 Jul 04. pii: 167. [Epub ahead of print]75(1):

Chronic intermittent hypoxia sustains the low-grade inflammatory memory of monocytes via activation of myelopoiesis.

Shi Qi Li, Yi Wang, Meng Yao Li, Liu Zhang, Xi Xi Chen, Ying Ni Lin, Li Na Zhou, Xian Wen Sun, Yong Jie Ding, Qing Yun Li.

   OBJECTIVE: Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), drives a chronic low-grade inflammatory state linked to multiple comorbidities. Monocytes play a pivotal role in the regulation of inflammatory responses. This study aimed to characterize the inflammatory profile of monocytes induced by CIH.
METHODS: Distribution and activation status of monocytes were analyzed in OSA versus healthy controls. In vivo, models of CIH were employed to assess the immediate and long-term effects on monocyte inflammatory profiles and bone marrow (BM) myelopoiesis.
RESULTS: Monocytes derived from OSA patients exhibited enhanced activation marker expression and cytokine secretion. In vivo, CIH provoked immediate inflammatory responses of peripheral monocytes, accompanied by increased abundance of hematopoietic stem and progenitor cells in the BM, resulting in enhanced myelopoiesis and increased circulating monocytes. After normoxic recovery, monocytes from CIH-exposed mice exhibited heightened inflammatory responses upon secondary challenge, which was associated with sustained, myeloid-biased myelopoiesis in the BM.
CONCLUSIONS: Our findings demonstrate that CIH sustains a low-grade inflammatory memory in monocytes, characterized by both basal activation and enhanced responsiveness to secondary stimulation. We identify the establishment of maladaptive myelopoiesis as a novel mechanism for the sustained inflammatory state in OSA, providing new insights into the pathogenesis of inflammatory responses and comorbidities associated with OSA.

Keywords:  Chronic intermittent hypoxia; Inflammatory memory; Monocytes; Myelopoiesis; Obstructive sleep apnea

DOI:  https://doi.org/10.1007/s00011-026-02321-7
Life Sci. 2026 Jul 06. pii: S0024-3205(26)00369-3. [Epub ahead of print] 124560

RPS20 phosphorylation acts as a molecular switch to integrate inflammatory and oxidative stress signals in sepsis.

Gang Yuan, Qudi Qiao, Ying Li, Jia Xu, Limin Cai, Hongyu Jie, Zhengzheng Yan.

  Sepsis is a life-threatening condition driven by dysregulated inflammation and oxidative stress, yet the role of ribosomal proteins in integrating these pathological signals remains poorly understood. Here, we identify ribosomal protein S20 (RPS20) as a phosphorylation-dependent switch coordinating inflammatory and oxidative stress responses in macrophages during sepsis. Proteomic analysis reveals thioredoxin (TXN) as the most dynamically altered RPS20 interactor upon LPS stimulation, with rapid complex dissociation and TXN nuclear translocation. Mechanistically, LPS-activated ERK1 directly phosphorylates RPS20 at T9 and S93. A phospho-ablative RPS20 mutant enhances RPS20-TXN binding, suppresses NLRP3 inflammasome activation, reduces ROS production, and attenuates pro-inflammatory cytokine secretion. Although RPS20 dephosphorylation does not affect NF-κB nuclear translocation, it selectively impairs p65 binding to specific gene promoters. In vivo, phosphorylation-deficient RPS20 ameliorates lung injury in septic mice. Collectively, RPS20 phosphorylation integrates inflammatory and oxidative signals, positioning RPS20 as a potential therapeutic target for sepsis.

Keywords:  ERK1; Inflammation; Oxidative stress; RPS20; TXN

DOI:  https://doi.org/10.1016/j.lfs.2026.124560
Epigenetics Chromatin. 2026 Jul 10.

Human Alu loci gain enhancer-type epigenetic modifications in monocytes during response to bacterial LPS.

Yonghao Pan, Kenji Ichiyanagi.

   BACKGROUND: Bacterial lipopolysaccharide (LPS) potently activates innate immunity. Transposable elements (TEs), particularly lineage-specific short interspersed elements (SINEs), have been implicated in immune regulatory evolution, yet their epigenomic roles during immune activation remain unclear.
RESULTS: Here, we reanalyzed published ChIP-seq data for H3K4me1, H3K4me3, and H3K27ac from human monocytes and mouse macrophage-like cells under basal and LPS-stimulated conditions. We identified widespread and dynamic activation of Alu-associated regulatory regions in human monocytes, accounting for around 15% of total enhancer-associated ChIP-seq peaks with and without LPS stimulation. In particular, over one quarter of the Alu-containing H3K4me1 and H3K27ac peaks appeared only after LPS stimulation. The Alu-containing enhancers that appeared in short treatment with LPS linked to many genes involved in the acute immune and inflammatory responses. On the other hand, prolonged LPS stimulation produced stronger chromatin activation at Alu loci that were linked to genes with more dispersed pathway associations, likely reflecting post-stimulation adaptation or tolerance.
CONCLUSIONS: These findings suggest that Alu elements act as regulatory scaffolds that shape the temporal and functional landscape of human immune responses. Our findings suggest that Alu elements, as primate-specific TEs, may contribute to heightened sensitivity to LPS by shaping species-specific enhancer landscapes.

Keywords:  Alu element; Enhancer regulation; Epigenomics; Innate immunity

DOI:  https://doi.org/10.1186/s13072-026-00686-x
Mol Metab. 2026 Jul 09. pii: S2212-8778(26)00102-X. [Epub ahead of print] 102418

Endurance Exercise Elicits a Hepatic Memory Associated with Improved Metabolic Function and Protein Secretion.

Yi-Heng Huang, Clay J Weidenhamer, Nasrin Dabirian, Mikaela Kasperek, Donald Molina, Samuel Deyhle, Subhashis Natua, Jaume Amengual, Jacob Matthew Allen, Auinash Kalsotra, Diego Hernández-Saavedra.

  Endurance exercise protects against metabolic dysfunction-associated steatotic liver disease (MASLD), yet whether these effects persist following cessation of training remains unclear. Here, we employed endurance training cycles in mice to isolate the hepatic memory of exercise. Our results indicate that endurance retraining potentiates systemic and hepatic glucoregulatory benefits. Exercise retraining persistently reduced hepatic steatosis, hallmarked by decreases in diacylglycerols and increased phosphatidylcholines (PC). Liver transcriptomic analysis identified lipid and protein secretory pathways induced by endurance retraining. Importantly, retraining enhanced hepatic expression of carboxylesterases, including Ces2b, Ces3a, Ces3b, and Ces4a, and increased circulating carboxylesterase activity and CES4A protein levels. Exercise retraining reduced serum LDL-c and increased HDL-c, while enhancing the delivery of lysoPC and PC, predicted targets of carboxylesterases, to the working muscle. Similarly, mice fed an obesogenic diet demonstrate that this hepatic memory of exercise persists under an obesogenic challenge. In humans, we show that a 6-week training period increases serum CES activity primarily in individuals with prior training. Lastly, our studies identify the PPAR-RXR-clock axis as a potential trigger that may engage the synchronized lipid delivery to skeletal muscle and support fatty acid oxidation. Together, these findings suggest that endurance retraining elicits a hepatic exercise memory characterized by persistent transcriptional reprogramming and lipid remodeling that restore metabolic benefits after inactivity and confer resilience against MASLD.

Keywords:  Liver memory; MASLD; PPARα; carboxylesterases; glucose metabolism; phosphatidylcholines

DOI:  https://doi.org/10.1016/j.molmet.2026.102418