bims-traimu 2026-06-07 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–06–07
eighteen papers selected by
Yantong Wan, Southern Medical University

Beta-Glucan modulates monocyte plasticity and differentiation capacity to mitigate DSS-induced colitis.
Trained immunity in inflammatory bone disease: a bibliometric and literature-level text-mining analysis.
Trained immunity agonists given to neonatal mice fail to protect against leptospiral infection in adulthood and may cause adverse effects.
Saccharomyces cerevisiae β-Glucan Training Induces a Nonclassical PGE2-High/NO-Low Macrophage Phenotype in Response to Pseudomonas aeruginosa Exopolysaccharide.
Lipid Droplet-Accumulating Microglia as a Therapeutic Node in Neurodegenerative Disease.
Viral-Induced autoimmune Disorders: Mechanistic insights and emerging concepts.
Widespread transcriptional memory shapes heritable states and functional heterogeneity in cancer and stem cells.
Neutrophil-derived itaconate facilitates tiered pulmonary inflammation via Kdm5b-associated epigenetic remodeling in alveolar macrophages.
Identification of a metabolic-immune crosstalk in Still's disease: monocyte/macrophage-derived immunometabolite itaconate dictates hepatic immunopathology via the CXCL10-CD8 T cell axis.
Trained immunity-primed DLL3-targeted CAR macrophages for the eradication of small cell lung cancer.
The autophagy-inhibitory tissue hormone DBI/ACBP contributes to the pathogenesis of multiple organ dysfunction syndrome in septic shock.
Therapeutic bacteria-trained NK cells confer long-term protection against cancer metastasis.
Mechanistic study of lipopolysaccharide-induced protection in macrophages against antitumor drugs.
Single-cell mapping of regulatory DNA-protein interactions.
Slfn4-mediated Stat3 signaling promotes suppressive bone marrow monocytes in a murine second-hit sepsis model.
Targeted silencing of CLYBL with platelet-mimetic siRNA nanoparticles drives itaconate-mediated macrophage reprogramming and protects against sepsis-triggered lung cell death.
Phosphorylated toll-like receptor 4 defines a high-risk sepsis endotype.
Nociceptive neurons inhibit neutrophil extracellular trap formation via MLKL-licensed histone release.

Elife. 2026 Jun 01. pii: RP107339. [Epub ahead of print]14

Beta-Glucan modulates monocyte plasticity and differentiation capacity to mitigate DSS-induced colitis.

Yinyin Lv, Yanyun Fan, Qingxiang Gao, Qiongyun Chen, Yiqun Hu, Lin Wang, Huaxiu Shi, Ermei Chen, Qinyu Xu, Ying Cai, Qingqi Fan, Linying Li, Dan Du, Jianlin Ren, Shih-Chin Cheng, Hongzhi Xu.

  Trained immunity involves the reprogramming of innate immune cells after an initial exposure, resulting in heightened inflammatory responses to subsequent stimuli and enhanced bactericidal capacity during infection. However, this pro-inflammatory state could also exacerbate chronic conditions like inflammatory bowel disease (IBD), which is characterized by persistent inflammation and microbial imbalance. It remains unclear how trained immunity influences IBD pathogenesis and whether it can be harnessed therapeutically. In our study, pretreatment with β-glucan reprogrammed bone marrow hematopoietic progenitors and peripheral monocytes, inducing a profound shift in monocyte plasticity and significantly reducing the severity of dextran sulfate sodium (DSS)-induced colitis. Adoptive transfer of bone marrow or peripheral monocytes from β-glucan-trained mice into naive mice conferred robust protection against colitis, demonstrating that this protective effect is transferable. Trained mice also displayed improved clearance of intestinal bacterial infections. Single-cell RNA sequencing revealed an expansion of reparative Cx3cr1+ macrophages derived from Ly6Chi monocytes, correlating with accelerated colonic epithelial regeneration. Collectively, these findings reveal how β-glucan-induced trained immunity modulates monocyte differentiation to ameliorate experimental colitis, highlighting the potential of harnessing trained immunity as a therapeutic strategy to recalibrate innate immune responses and restore gut homeostasis in IBD, shedding light for future clinical applications.

Keywords:  IBD; immunology; inflammation; inflammatory bowel disease; monocyte/macrophage; mouse; trained immunity

DOI:  https://doi.org/10.7554/eLife.107339
Front Immunol. 2026 ;17 1832996

Trained immunity in inflammatory bone disease: a bibliometric and literature-level text-mining analysis.

Zihang Zhao, Zihan Liu, Liang Guo, Teng Pan, Ruoyu Wang, Yiran Li, Yingchao Yin, Ruipeng Zhang, Zhiyong Hou.

   Background: Trained immunity provides a framework for understanding persistent innate immune reprogramming in chronic inflammatory and immune-mediated disorders. Its relationship with osteoimmunology and inflammatory bone disease, however, remains insufficiently characterized.
Methods: We performed a bibliometric and literature-level text-mining analysis using WoSCC as the primary source for formal bibliometric analyses. A two-corpus design was used, with a core corpus for disease-focused bibliometric analysis and an extended corpus for semantic screening and sensitivity analyses. Scopus and PubMed were queried independently for cross-database comparison. Topic modeling, TF-IDF-based semantic screening, disease-context analysis, and bridge-network mapping were used to summarize literature-level patterns.
Results: The core corpus included 83 records, and the extended corpus included 301 records. Within the full-year 2013-2025 comparison window, publication output increased over time and reached its highest level in 2025. Cross-database comparison showed broadly concordant publication trends and substantial DOI-level overlap across WoSCC, Scopus, and PubMed. Periodontitis was the most prominent disease context, whereas osteoarthritis, ankylosing spondylitis, osteoporosis, and inflammatory arthritis also appeared in the disease-context mapping. Across bibliometric, semantic, and mapping analyses, recurrent literature-level patterns involved myeloid-cell reprogramming, epigenetic and metabolic remodeling, macrophage- and monocyte-associated terms, myelopoiesis, innate immune signaling, and osteoclast-related pathways.
Conclusion: Research on trained immunity in inflammatory bone disease remains relatively small but is expanding. Current literature most consistently connects trained-immunity-related concepts with myeloid reprogramming, immunometabolic and epigenetic processes, periodontitis, and inflammatory bone remodeling. These findings provide a structured literature-level overview of an emerging field and may help guide future mechanistic, experimental, and translational studies.

Keywords:  epigenetic reprogramming; inflammatory bone disease; innate immune memory; myelopoiesis; osteoclastogenesis; osteoimmunology; periodontitis; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2026.1832996
Innate Immun. 2026 Jan-Dec;32:32 17534259261455983

Trained immunity agonists given to neonatal mice fail to protect against leptospiral infection in adulthood and may cause adverse effects.

Mégane Fernandez, Frédérique Vernel-Pauillac, Tiffany Pezier, Sonia Lacroix-Lamandé, Catherine Werts.

  Background and ObjectivesTrained immunity (TI) refers to a non-specific, long-lasting protective immune response that occurs following initial stimulation of the immune system and thought to be largely mediated by functional reprogramming of myeloid cells. TI has been demonstrated in BCG-vaccinated infants and can be induced in human cells and adult mice via agonists of pattern recognition receptors (PRR), such as β-glucan or MDP (a muropeptide that activates NOD2). However, its induction in neonates remains poorly understood. Previously, we demonstrated that the synthetic TLR2-NOD2 dual agonist CL429 enhances antimicrobial functions in adult mice and protects against subsequent infection with Leptospira interrogans, a zoonotic pathogen. We also demonstrated the immediate protective benefits of NOD2 stimulation in neonates against Cryptosporidium, a zoonotic pathogen that affects young animals in livestock herds. However, whether NOD2 agonists can induce TI in neonates and protect them at adulthood is unknown.Methods and ResultsHere, we investigated whether exposure of neonatal mice to PRR agonists (CL429, MDP or β-glucan), administered intraperitoneally at one week interval at 7/14 or 14/21 days of age, could enhance inflammatory cytokines production after ex vivo restimulation and confer long-term protection into adulthood. Surprisingly, none of the treatments enhanced ex vivo cytokine responses in adulthood after restimulation, nor did they confer protection against experimental leptospirosis. Instead, MDP-treated neonates exhibited 50% mortality following adult infection, revealing an unexpected detrimental effect.ConclusionThese findings demonstrate that these PRR agonists fail to induce protective TI against Leptospira when administered to neonatal mice, challenging assumptions derived from adult models. Furthermore, our study reveals the risks of administering immunostimulants during the early stages of life, and highlights unanticipated and potentially harmful, PRR- and age-specific mechanisms of immune system modulation.

Keywords:  NOD2; leptospirosis; macrophages; neonatal mice; trained immunity

DOI:  https://doi.org/10.1177/17534259261455983
Arch Immunol Ther Exp (Warsz). 2026 Jan 01. 74(1):

Saccharomyces cerevisiae β-Glucan Training Induces a Nonclassical PGE2-High/NO-Low Macrophage Phenotype in Response to Pseudomonas aeruginosa Exopolysaccharide.

Marta Ciszek-Lenda, Grzegorz Majka, Maciej Suski, Sabina Górska, Edyta Golińska, Izabela Siemińska, Rafał Olszanecki, Magdalena Strus, Janusz Marcinkiewicz.

  Exopolysaccharide (EPS), a major constituent of Pseudomonas aeruginosa biofilms, protects bacteria from M1-macrophage-mediated clearance while promoting chronic inflammation. This study investigated how Saccharomyces cerevisiae β-glucan (BG)-induced macrophage training reshapes subsequent inflammatory and antimicrobial responses to EPS. Peritoneal macrophages from C57BL/6 mice were trained in vitro with BG and subsequently stimulated with EPS purified from a clinical P. aeruginosa isolate obtained from a patient with severe cystic fibrosis. Cytokines, prostaglandin E2 (PGE2), and nitric oxide (NO) were quantified, and global proteomic profiling was performed. BG training amplified EPS-induced secretion of TNF-α, IL-6, and additional pro-inflammatory mediators. Trained macrophages also showed markedly increased PGE2 production, minimal NO release, and reduced phagocytic activity. Proteomic analyzes confirmed upregulation of PGE2-biosynthetic enzymes and suppression of inducible NO synthase, along with enhanced expression of antimicrobial and immunoregulatory factors, including platelet factor 4, antileucoproteinase, C1q components, and selected chemokines. These data reveal a previously uncharacterized macrophage state-neither M1 nor M2-emerging specifically from BG training and defined by high PGE2 and low NO production in response to EPS. S. cerevisiae BG training reprograms EPS-stimulated macrophages toward a distinct, non-classical trained-immunity phenotype characterized by elevated PGE2 and suppressed NO production. This newly defined phenotype represents a novel form of trained immunity and highlights the dual proinflammatory and immunoregulatory roles of macrophage-derived PGE2. These findings suggest that targeted macrophage reprogramming may offer a promising therapeutic strategy for mitigating P. aeruginosa biofilm-driven chronic inflammation, including in cystic fibrosis.

Keywords:  Inflammation; NO; P. aeruginosa EPS; PGE2; Saccharomyces cerevisiae β-glucan; Trained macrophages

DOI:  https://doi.org/10.2478/aite-2026-0014
ACS Chem Neurosci. 2026 Jun 02.

Lipid Droplet-Accumulating Microglia as a Therapeutic Node in Neurodegenerative Disease.

Siqi Guo, Qingyu Zhang, Rui Guo, Liyuan Fu, Huaxu Zhu, Qichun Zhang.

  Neurodegenerative disorders increasingly reflect failures of cellular state control rather than the linear accumulation of a single toxic lesion. Microglia become trapped in maladaptive states in which inflammatory activation is decoupled from effective cargo processing. Lipid droplet-accumulating microglia (LDAM) represent a recurrent convergence state across aging and neurodegeneration, characterized by persistent neutral lipid sequestration, reduced phagocytosis-to-degradation capacity, oxidative amplification, and chronic but functionally inefficient inflammation. LDAM emerges when lipid substrate influx exceeds the capacity of cholesterol efflux, lysosomal lipophagy, and mitochondrial β-oxidation, converting lipid droplets from transient buffers into stable metabolic anchors. This entrenchment is reinforced by mitochondrial exhaustion, vacuolar H+-ATPase-linked lysosomal deacidification, and inflammasome/interferon locking, often further amplified by cGAS-STING signaling. Together, these constraints converge on a state of metabolic-epigenetic locking that sustains permissive chromatin landscapes at pro-inflammatory loci. On this basis, state-resetting strategies are considered that rebalance lipid flux, restore organelle clearance capacity, and transiently restrain inflammatory amplification, while spatial multiomics and fluid biomarkers are discussed as candidate tools for stage- and niche-resolved stratification of combination interventions.

Keywords:  lipid droplet-accumulating microglia; lipid flux; lysosomal lipophagy; trained immunity

DOI:  https://doi.org/10.1021/acschemneuro.6c00284
Hum Immunol. 2026 Jun 05. pii: S0198-8859(26)00111-4. [Epub ahead of print]87(8): 111765

Viral-Induced autoimmune Disorders: Mechanistic insights and emerging concepts.

Aruna Rajalingam, Anjali Ganjiwale.

  Autoimmune disorders (ADs) result from a complex interaction of genetic predisposition and environmental triggers, with viral infections identified as primary causes. This review summarizes current evidence on how viruses-including Epstein-Barr Virus (EBV), Enteroviruses, and SARS-CoV-2-initiate and worsen autoimmunity. We explore established mechanisms such as molecular mimicry, bystander activation, and epitope spreading, while highlighting the emerging roles of maladaptive trained immunity and cytokine storms in chronic inflammation. Additionally, we discuss the bidirectional relationship between gut microbiota dysbiosis and virus-induced immune failure. Understanding these layered interactions is crucial for developing biomarker-driven diagnostic and treatment strategies.

Keywords:  Cytokine storm; Gut microbiota dysbiosis; Maladaptive trained immunity; Molecular mimicry; Viral infections; Virus-induced autoimmunity

DOI:  https://doi.org/10.1016/j.humimm.2026.111765
Cell Syst. 2026 Jun 04. pii: S2405-4712(26)00103-1. [Epub ahead of print] 101621

Widespread transcriptional memory shapes heritable states and functional heterogeneity in cancer and stem cells.

Yongjie Lin, Xiangru Chen, Long Wu, Yutong Zhou, Yihan Lin.

  Recent studies show that non-genetic heterogeneity, particularly through heritable cell states, shapes cancer evolution and developmental trajectories. However, single-cell snapshots lack temporal information to identify these states. We employ lineage-resolved single-cell transcriptomics to map heritable cell states that persist across divisions, distinguishing them from transient fluctuations. We reveal that heritable states are underpinned by widespread transcriptional memory, whereby heritable gene expression defines two classes of states: clustered states, characterized by clustered gene expression, and latent states, marked by non-clustered gene expression. This memory shows partial conservation across cell types and conditions and appears to be maintained by robust epigenetic mechanisms that are resistant to environmental perturbations. Functionally, memory genes predict critical behaviors, including metastatic potential and lineage commitment, with latent-state genes often outperforming clustered-state genes. Our findings establish transcriptional memory as a potential basis for heritable cellular heterogeneity, providing a framework for understanding functional cellular variation across biological systems.

Keywords:  CORAL; cancer; cellular heterogeneity; heritable cell state; lineage tracing; memory genes; single-cell transcriptomics; stem cells; transcriptional memory

DOI:  https://doi.org/10.1016/j.cels.2026.101621
Cell Rep. 2026 Jun 02. pii: S2211-1247(26)00490-0. [Epub ahead of print]45(6): 117412

Neutrophil-derived itaconate facilitates tiered pulmonary inflammation via Kdm5b-associated epigenetic remodeling in alveolar macrophages.

Gyumin Lim, Juyeon Kim, Doyoung Park, Jeong Hee Lee, Yeon Jin Roh, Moses Yang, Soowan Lee, Seungbok Yang, Sojeong Baek, Jumi Park, Hae Chan Lim, Ji-Hyeon Lee, Sehan Kim, Hwiwon Seo, Yong-Hoon Kim, Su Myung Jung, Hanseul Yang, Pureum Sun, Seong Eun Lee, Yea Eun Kang, Young-Jun Park, Young Min Son, Hyon-Seung Yi, Jun Young Hong, Luis F Moita, Da Hyun Kang, Hongsook Kim, Chuna Kim, Sung-Jin Yoon, Dong Wook Choi.

  Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), present a substantial clinical burden, magnified by conditions such as COVID-19. While these conditions provide a model for exploring complex inflammatory processes, the environmental factors coordinating these responses remain poorly understood. Here, we employ comprehensive multi-omics and biochemical analyses and identify neutrophil-derived itaconate as an extracellular factor associated with sequential immune cell infiltration, including neutrophils, T cells, and monocytes. Mechanistically, extracellular itaconate metabolically facilitates Kdm5b-associated epigenetic changes at the Il6, Ccl5, and Cxcl10 gene promoters in alveolar macrophages, which are important for immune cell recruitment. Consistent with this, Mrp8-Cre Acod1fl/fl mice lacking neutrophil-derived itaconate are significantly protected from ALI-induced inflammation, with similar patterns observed in an Acinetobacter baumannii infection model. Collectively, these findings identify neutrophil-derived itaconate as an environmental factor that epigenetically shapes tiered inflammatory responses in the lung.

Keywords:  ALI; AMs; CP: immunology; CP: metabolism; Itaconate; KDM5B; Lung Inflammation; acute lung injury; alveolar macrophages; environmental factor; lysine demethylase 5b; neutrophils

DOI:  https://doi.org/10.1016/j.celrep.2026.117412
Exp Mol Med. 2026 Jun 05.

Identification of a metabolic-immune crosstalk in Still's disease: monocyte/macrophage-derived immunometabolite itaconate dictates hepatic immunopathology via the CXCL10-CD8 T cell axis.

Junna Ye, Fan Wang, Zhuochao Zhou, Jinchao Jia, Ziang Wu, Yijun You, Nadiem Atiq, Yutong Su, Huihui Chi, Jianfen Meng, Mengyan Wang, Yuning Ma, Shirin Hosseini, Martin Korte, Jialin Teng, Chengde Yang, Karsten Hiller, Qiongyi Hu, Wei He, Yue Sun.

Still's disease (SD) is a chronic and systemic autoinflammatory disorder, with the possibility of resulting in life-threatening complications, including macrophage activation syndrome (MAS). The metabolic-immune interplay underlying the immunopathology of SD/MAS remains largely unexplored. In this study, we identified itaconate - a myeloid cell-specific metabolite derived from the tricarboxylic acid cycle via the enzyme ACOD1 - as a dual regulator of inflammation and chemokine-driven tissue injury in SD/MAS. Clinical metabolomics revealed elevated serum itaconate in patients with SD, attributable to peripheral blood monocytes and correlated with disease severity. This was consolidated by the identification of the Acod1-itaconate axis in monocytes and macrophages in both a mouse model of MAS and in vitro cell cultures. Although itaconate suppressed IL-1β, IL-6, CXCL1 and CCL2 in vitro, it paradoxically amplified CXCL10 secretion in vitro and in vivo. This was in line with the observations of elevated plasma CXCL10 levels in patients with MAS. In the CpG ODN 1826-induced MAS mouse model, ablation of Acod1 ameliorated disease manifestations and hepatic inflammation, accompanied by a reduced CXCL10 level as well as attenuated hepatic infiltration of CD8+ T cells. Collectively, our study reveals a previously unrecognized metabolic-immune crosstalk in AOSD/MAS, positioning monocyte/macrophage-derived itaconate as a dual regulator that suppresses canonical pro-inflammatory cytokines while licensing CXCL10-mediated CD8+ T cell-driven tissue injury. Therefore, discovery from this study calls for scrutiny of an itaconate-based anti-inflammatory strategy in chronic inflammatory diseases.

DOI: https://doi.org/10.1038/s12276-026-01751-x
J Adv Res. 2026 Jun 01. pii: S2090-1232(26)00443-1. [Epub ahead of print]

Trained immunity-primed DLL3-targeted CAR macrophages for the eradication of small cell lung cancer.

Hangjie Ying, Yazhou Wang, Na Li, Wenshuo Ma, Xin Shou, Zhiyun Liu, Changjiang Chen, Zhenzhen Dong, Hung-Wing Li, Junfeng Zhang, Ying Jin, Sergei Krasny, Liyun Shi.

   BACKGROUND: Small cell lung cancer (SCLC) is highly malignant with limited treatment options. Chimeric antigen receptor macrophages (CAR-Ms) show potential for solid tumor therapy due to their phagocytic activity, tissue penetration, and immunomodulatory functions, but their application in SCLC remains unexplored. Delta-like ligand 3 (DLL3), a SCLC-specific membrane antigen, represents a promising therapeutic target. Here, we developed a DLL3-targeted CAR-M therapy and an enhanced strategy for SCLC immunotherapy.
METHODS: DLL3-specific CAR-Ms were generated by introducing a CAR construct (DLL3-ScFv-CD8-CD3ζ) into murine and human macrophages via lentiviral transduction. A β-glucan (BG)-based training protocol was established to enhance CAR-M functionality. Phagocytic and cytotoxic activities were evaluated by flow cytometry and bioluminescence assays, and in vivo antitumor efficacy was assessed in immunodeficient and immunocompetent mouse models.
RESULTS: Engineered CAR-Ms exhibited potent phagocytic and cytotoxic activity against DLL3-positive cells and effectively infiltrated and eliminated tumor spheroids in 3D culture systems. Intravenously administered CAR-Ms suppressed DLL3-positive lung cancer growth in both immunodeficient and immunocompetent models without discernible toxicity. Importantly, BG training enhanced CAR-M functionality by conferring sustained anti-tumor immunity, amplifying inflammatory and interferon pathway activation, and remodeling the tumor microenvironment through epigenetic and metabolic reprogramming. These findings establish BG-trained, DLL3-targeting CAR-Ms as a promising therapeutic approach for SCLC.
CONCLUSION: Anti-DLL3 CAR-Ms demonstrate significant potential for solid tumor treatment and may offer a viable clinical strategy for SCLC in the future.

Keywords:  Chimeric antigen receptor; Delta-like protein 3; Macrophage; Small cell lung cancer; Trained immunity

DOI:  https://doi.org/10.1016/j.jare.2026.05.047
Autophagy. 2026 Jun 01. 1-4

The autophagy-inhibitory tissue hormone DBI/ACBP contributes to the pathogenesis of multiple organ dysfunction syndrome in septic shock.

Flavia Lambertucci, Maria Chiara Maiuri, Isabelle Martins, Guido Kroemer.

  Systemic microbial infection leading to septic shock with multiple organ dysfunction syndrome (MODS) is a major cause of mortality and represents a substantial unmet medical need. We recently observed that, compared with uninfected controls, patients with septic shock exhibit significantly elevated circulating concentrations of the tissue hormone acyl-CoA binding protein (ACBP), encoded by the diazepam binding inhibitor (DBI) gene, a potent inhibitor of autophagy. Increased plasma DBI/ACBP levels correlated with disease severity and poor clinical outcome. Similarly, DBI/ACBP concentrations were elevated in three distinct mouse models of septic shock induced by (i) bacterial lipopolysaccharide injection, (ii) inoculation with monomicrobial Escherichia coli or (iii) polymicrobial sepsis following cecal ligation and puncture. In all three models, neutralization of DBI/ACBP using specific monoclonal antibodies significantly reduced mortality. Comprehensive behavioral, cardiac, pulmonary, hepatic, renal and splenic phenotyping further demonstrated that DBI/ACBP neutralization alleviated all hallmarks of MODS, including impaired thermoregulation, lethargy and organ failure affecting the heart, lungs, liver and kidneys. Multi-omics analyses, including bulk transcriptomics, metabolomics and high-dimensional immunophenotyping, revealed that DBI/ACBP neutralization attenuated sepsis-associated alterations in gene expression, metabolism and myeloid cell infiltration across major organs. Mechanistically, DBI/ACBP inhibition enhanced organ resistance to lipopolysaccharide-induced sterile inflammation while simultaneously promoting bacterial clearance by macrophages and granulocytes both in vivo and in vitro in models of monomicrobial and polymicrobial sepsis. Collectively, these findings identify DBI/ACBP as a pathogenic mediator of sepsis, consistent with its previously described anti-autophagic, immunosuppressive, pro-inflammatory and pro-senescent properties.

Keywords:  Bacterial infection; biomarker; hyperinflammation; multiorgan failure; viral infection

DOI:  https://doi.org/10.1080/15548627.2026.2673174
Mol Ther. 2026 Jun 03. pii: S1525-0016(26)00467-3. [Epub ahead of print]

Therapeutic bacteria-trained NK cells confer long-term protection against cancer metastasis.

Li Rong, Jingchu Hu, Wei Jin, Renhao Li, Yangfan Wu, Nan Zhou, Xiaoyu Zhao, Zhongjun Zhou, Hosen Shakhawat, Xiaolei Wang, Shuo Han, Huarui Gong, Xuansheng Lin, Wenjun Li, Yige He, Sukbum Kim, Qiubin Lin, Jian-Dong Huang.

Metastasis causes 90% of cancer-related deaths, yet preventive strategies remain limited. Here, we report that a single dose of therapeutic Salmonella, a prominent anti-tumor bacterial therapy, provides long-lasting protection against metastasis in mice by inducing "trained" Natural Killer (NK) cells. Integrated functional and multi-omics analyses revealed that Salmonella-trained NK (stNK) cells establish an enduring reprogrammed epigenome characterized by enhanced pro-survival signaling and immune effector functions, resulting in more potent IFN-γ release and cytotoxicity upon secondary stimulation. We further showed that this training requires a transient pulse of IL-12 combined with sustained IL-18 signaling. Crucially, stNK cells significantly outperform conventional immune checkpoint therapies, including PD-1 and TIGIT blockade, in preventing metastasis, underscoring the unique immunological mechanisms in combating metastasis. These findings highlight the potential of bacterial cancer vaccines or trained NK cells as effective strategies for metastasis prevention.

DOI: https://doi.org/10.1016/j.ymthe.2026.05.023
Int J Biol Macromol. 2026 May 29. pii: S0141-8130(26)02722-4. [Epub ahead of print]370 152795

Mechanistic study of lipopolysaccharide-induced protection in macrophages against antitumor drugs.

Zhangwei Qiao, Yuan Wang, Zhengchao Wang, Meicai Su, Haifei Lv, Xiaobin Hao, Kaitao Li, Xiao Tian, Shuliang Song, Qiyong Huai.

  Cancer has become the leading cause of death, and chemotherapy remains the mainstay of treatment. However, chemotherapeutic agents are less selective and their cytotoxicity can damage immune cells, including macrophages, affecting patient survival. Lipopolysaccharide (LPS) in vivo elicits a range of immune responses and thus plays a role in the immune system. This study aimed to investigate the mechanism of the protective effect of LPS against macrophage damage caused by antitumor drugs. Here, we found that LPS protects macrophages from antitumor drug-induced damage, while no comparable protective effect was observed in tumor cells. There was no significant difference in cell viability after inhibition of Toll-like receptor 4 (TLR4) and caspase-11, canonical receptors for LPS. Given the central role of oxidative stress in antitumor drug-induced cytotoxicity, we investigated whether solute carrier (SLC) family-mediated amino acid transport contributes to the protective effects of LPS. qRT-PCR analysis showed that LPS significantly upregulated SLC3A2 and SLC7A11, two genes essential for the function of system Xc- (the cystine/glutamate antiporter), which regulates glutathione (GSH) synthesis. Treatment of the ADR + LPS group with the system Xc- inhibitor erastin or the ABCC1 inhibitor MK571 significantly reduced macrophage viability, decreased SLC7A11 expression, and lowered intracellular GSH levels. These results suggest that LPS may promote system Xc--dependent GSH synthesis and is associated with ABCC1-mediated drug transport, thereby contributing to the protection of macrophages like RAW264.7 from drug-induced damage. This study elucidates LPS-mediated protective mechanisms and provides mechanistic insight that may help identify safer therapeutic strategies.

Keywords:  Lipopolysaccharide; Macrophage; System Xc(−)

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152795
Cell. 2026 Jun 04. pii: S0092-8674(26)00573-8. [Epub ahead of print]

Single-cell mapping of regulatory DNA-protein interactions.

Wei-Yu Chi, Sang-Ho Yoon, Evrim Goksel, Levan Mekerishvili, Joe Pelt, Yiyun Lin, Tamara Prieto, John Zinno, Saravanan Ganesan, Catherine Potenski, Franco Izzo, Dan A Landau, Ivan Raimondi.

  Gene expression is controlled by transcription factors (TFs), whose genome binding is shaped by chromatin accessibility and histone modifications, yet mapping these interactions, particularly those with weak affinity or a transient nature, in single cells remains technically challenging. To address this gap, we developed docking and deamination followed by sequencing (D&D-seq), a single-cell immuno-tethering technology for profiling DNA-protein interactions. D&D-seq couples an antibody-binding nanobody to a cytosine base editor, a combination that enables detection of weak or transient factor binding through targeted cytosine-to-uracil editing at protein-bound genomic sites. This approach is compatible with standard single-cell multi-omic workflows and therefore allows integrated analyses of gene regulation. Using assay for transposase-accessible chromatin using sequencing (ATAC-seq) and single-cell ATAC-seq (scATAC-seq), we assessed chromatin accessibility as a functional readout of TF activity, and by coupling D&D-seq with whole-genome sequencing, we captured CTCF binding in both active and inactive chromatin compartments.

Keywords:  clonal hematopoiesis; epigenomics; gene regulation; single-cell; transcription factors

DOI:  https://doi.org/10.1016/j.cell.2026.05.014
Mol Med. 2026 Jun 01.

Slfn4-mediated Stat3 signaling promotes suppressive bone marrow monocytes in a murine second-hit sepsis model.

Xiaoyan Meng, Huawei Wei, Jiao Cai, Yiman Han, Haowei Wang, Yutong Yang, Lei Peng, Xingying He, Hongbin Yuan.

   BACKGROUND: Sepsis survivors who develop recurrent or secondary infections often exhibit prolonged immunosuppression and impaired pathogen clearance, yet the underlying mechanisms remain poorly defined and targeted therapies are limited.
METHODS: We established a murine second-hit sepsis model to examine immune remodeling during the immunosuppressive phase after an initial inflammatory insult. Bone marrow immune remodeling was characterized by flow cytometry and single-cell RNA sequencing. Purified myeloid subsets were subjected to functional assays, transcriptomic analyses, and molecular studies to define how Slfn4 regulates the suppressive program of monocytic myeloid-derived suppressor cell-like (M-MDSC-like) cells.
RESULTS: We found that Slfn4 marks an immunosuppressive M-MDSC-like subset in the bone marrow during second-hit sepsis, and our data support a role for the Slfn4-Stat3 axis in maintaining its suppressive phenotype. Genetic silencing of Slfn4 or pharmacologic inhibition of Stat3 was associated with reduced M-MDSC-like cell abundance, partially restored T-cell function, and improved survival. Mechanistically, our data supports a model in which SLFN4 enhances Stat3 activation in association with post-transcriptional repression of Socs3, potentially through interaction with an AU-rich element within the Socs3 3'-UTR. In addition, sildenafil, a PDE5 inhibitor, decreased M-MDSC-like cell abundance and enhanced bacterial clearance in vivo.
CONCLUSIONS: These findings implicate the Slfn4-Stat3 axis in bone marrow-associated immunosuppression in this murine second-hit sepsis model and support further investigation of this pathway in the late immunosuppressive phase of sepsis.

Keywords:  Bone marrow; M-MDSCs; Second-hit sepsis; Slfn4; Stat3 signaling

DOI:  https://doi.org/10.1186/s10020-026-01515-3
Cell Death Discov. 2026 May 30.

Targeted silencing of CLYBL with platelet-mimetic siRNA nanoparticles drives itaconate-mediated macrophage reprogramming and protects against sepsis-triggered lung cell death.

ZuoJun Huang, Jialin Zhong, Li Zhang, Xianggui Huang, Shanshan Liang, Youfeng Zhu, Rui Zhang, Hongzhi He, Chengcheng Xu, Wang Chen, Jing Wang, Xiaolong Wu, Yumin Liang, Jian Zou, Shuyao Zhang.

Excessive inflammation and metabolic dysregulation fuel alveolar cell death in sepsis-induced lung injury, yet effective molecular interventions are lacking. We identify citrate lyase beta-like (CLYBL) as a previously unrecognized metabolic driver of macrophage-mediated tissue damage. In a murine cecal ligation and puncture model, CLYBL was strongly upregulated in lung tissue and peritoneal macrophages. To therapeutically target this pathway, we engineered platelet-derived extracellular vesicle-coated poly(lactic-co-glycolic acid) nanoparticles (PEVs@PLGA) encapsulating CLYBL-specific small interfering RNA. This platelet-mimetic system enabled efficient, biocompatible delivery of siRNA and robust CLYBL knockdown both in vitro and in vivo. CLYBL silencing triggered accumulation of the anti-inflammatory metabolite itaconate, limited M1 macrophage polarization, and preserved alveolar epithelial integrity, thereby reducing cell death and improving pulmonary repair. Transcriptomic analysis revealed broad immunometabolic remodeling consistent with enhanced resolution of inflammation. Biosafety evaluation confirmed negligible systemic toxicity. These findings uncover CLYBL as a critical metabolic checkpoint linking macrophage activation to alveolar cell death and highlight platelet-mimetic siRNA nanoparticles as a potent therapeutic strategy. Our work provides a mechanistic and translational framework for targeting macrophage immunometabolism to prevent fatal organ damage during sepsis.PEVs@PLGA@si-CLYBL promote itaconate accumulation, induce immune cell functional remodeling, and facilitate lung epithelial repair, offering a novel therapeutic approach for sepsis-induced lung injury (Created with BioRender.com).

DOI: https://doi.org/10.1038/s41420-026-03119-6
Crit Care. 2026 May 30. pii: 285. [Epub ahead of print]30(1):

Phosphorylated toll-like receptor 4 defines a high-risk sepsis endotype.

SepsisDataNet.NRW research group

   BACKGROUND: Sepsis is a life-threatening condition characterized by a dysregulated immune response to infection. Toll-like receptor 4 plays a central role in pathogen recognition and inflammatory signalling and has been considered a key driver of sepsis pathophysiology. Pharmacological inhibition of this receptor showed beneficial effects in experimental models but failed in clinical trials. We therefore aimed to quantify in vivo activation of Toll-like receptor 4 in patients with sepsis and to determine its association with 30-day survival.
METHODS: Peripheral blood mononuclear cells were obtained from 100 patients with sepsis enrolled in the SepsisDataNet.NRW cohort. Samples were collected on day 1 (within 36 h after diagnosis) and day 4. Activation of TLR4 was quantified by measuring receptor phosphorylation using a validated proximity ligation assay. Survival analyses were performed using Kaplan-Meier curves and Cox proportional hazards regression models to assess the association between receptor activation and 30-day mortality.
RESULTS: Overall activation of TLR4 was low, with median values below one signal per cell at both day 1 and day 4. Despite the generally low levels, a subgroup of patients showed increased receptor activation. Higher activation was associated with significantly reduced 30-day survival. Patients with elevated activation had a higher risk of death both at day 1 (HR 2.03, 95% CI 1.01-4.07, p = 0.048) and day 4 (HR 2.77, 95% CI 1.14-6.73, p = 0.025). This association remained significant after adjustment for SOFA score at admission, age, infection focus and sex in multivariable Cox regression analysis (p = 0.006).
CONCLUSIONS: In vivo activation of TLR4 is not uniformly present in patients with sepsis but occurs only in a subset of individuals. In those patients, increased activation is strongly associated with mortality. These findings suggest the presence of a distinct high-risk sepsis endotype characterized by enhanced receptor activation. This may help explain the failure of previous clinical trials of TLR4 inhibitors and supports the concept of biomarker-guided precision medicine approaches in sepsis.
TRIAL REGISTRATION: German Clinical Trials Register (DRKS), DRKS00018871, retrospectively registered on 14 November 2019.

Keywords:  30-day-survival; Endotype; Precision medicine; Proximity ligation assay; Sepsis; SepsisDataNet.NRW; TLR4 phosphorylation; TLR4 receptor

DOI:  https://doi.org/10.1186/s13054-026-06115-5
Cell Rep. 2026 Jun 01. pii: S2211-1247(26)00535-8. [Epub ahead of print]45(6): 117457

Nociceptive neurons inhibit neutrophil extracellular trap formation via MLKL-licensed histone release.

Han Meng, Wenchao Hu, Enming Kang, Qing Xu, Pengfei Wang, Xuyang Yi, Honghui Mao, Bowen Zhang, Xinyu Meng, Yanjin Wang, Yanchen Tan, Zhuqing Mao, Xingxing Zheng, Lina Niu, Ming Shi, Ceng Luo, Shengxi Wu, Rougang Xie, Yazhou Wang.

  Neutrophil-involved neuroinflammation in dorsal root ganglion (DRG) plays double-sword roles in chronic pain. How DRG neuron-neutrophil interaction contributes to chronic pain remains unclear. Here, we report that MLKL, a key molecule in necroptosis, is constitutively expressed in the nucleus of nociceptive neurons and binds to histone H3. Periphery inflammation disrupted MLKL/H3 interaction, leading to cytoplasmic translocation of MLKL and release of histone H3. Extracellular histone H3 induces neuronal hyperactivity, neutrophil extracellular trap (NET), and hyperalgesia, possibly through P2X7 receptor and Toll-like receptor 4. Nociceptive-specific depletion of Mlkl significantly decreased pain threshold and exacerbated NET formation independent of cell death. Neutralizing extracellular histone, clearing extracellular DNA or restoring nuclear localization of MLKL can reduce both NET formation and hyperalgesia in Mlkl-/-mice. These data demonstrated that the nociceptive neuron-neutrophil interaction mediated by this MLKL-histone-NET cascade may serve as a potential therapeutic target for chronic inflammatory pain.

Keywords:  CP: neuroscience; MLKL; histone; inflammatory pain; neutrophil extracellular trap

DOI:  https://doi.org/10.1016/j.celrep.2026.117457