bims-traimu 2026-05-03 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–05–03
eighteen papers selected by
Yantong Wan, Southern Medical University

Inactivated Klebsiella pneumoniae Induces Metabolic and Hematopoietic Reprogramming to Promote Trained Immunity and Heterologous Antibacterial Protection.
Bletilla striata polysaccharide as a dual-hit biologic: Orchestrating pyroptosis inhibition and trained immunity for chronic wound resolution.
Microglial Innate Immune Memory: Implications and Research Advances in Central Nervous System Disorders.
Epigenetic reprogramming in tuberculosis: mechanisms of immune evasion and host-directed therapies.
Immuno-inflammatory-metabolic interactions in cardiovascular diseases: a review from basic mechanisms to clinical translation.
RanGAP1 plays a vital role in anti-infective functions of macrophages and sepsis progression.
Transcriptome analysis revealed immune protection conferred by bath vaccination with formalin-killed Vibrio parahaemolyticus on Penaeus vannamei.
IL-2-TGFβ co-agonist induces immune tolerance.
Chac1 deficiency confers sepsis resistance by enriching gut microbiota-derived indole-3-carboxylic acid to drive macrophage metabolic shifts.
MPC1 regulates endotoxin tolerance of macrophages through mitochondrial oxidative stress resistance.
BRD4 modulates antimicrobial defense via non-canonical NRF2 activation in macrophages to confer protection against sepsis.
Secreted phospholipase PLA2G5 acts as a hemolytic factor in sepsis.
d-amino acids restrain macrophage IL-1β release through gasdermin D acetylation.
Toll-like receptors in innate immunity and inflammation: from fundamental biology to clinic insights.
Measurement and quantification of macrophage lytic cell death by kinetic microscopy.
RPSA-OLFM4 axis governs neutrophil migration against bacterial infection and sepsis.
A Muribaculaceae-enriched microbiota exacerbates TLR4-dependent Acinetobacter baumannii-induced hyperinflammatory sepsis.
Lipopolysaccharide uptake is augmented in lipopolysaccharide-tolerant mouse macrophage-like cells via increased CD14 expression.

Vaccines (Basel). 2026 Mar 27. pii: 300. [Epub ahead of print]14(4):

Inactivated Klebsiella pneumoniae Induces Metabolic and Hematopoietic Reprogramming to Promote Trained Immunity and Heterologous Antibacterial Protection.

Xiang Cheng, Shaoqiong Huang, Zhidong Hu, Xiaoyong Fan.

   BACKGROUND: Infections caused by multidrug-resistant bacteria and inadequate vaccine coverage against opportunistic pathogens highlight the need for interventions that broadly and durably enhance host defense beyond antigen-specific adaptive immunity. Trained immunity, driven by metabolic and epigenetic reprogramming of innate immune cells, has been predominantly characterized using Bacille Calmette-Guérin and β-glucan, whereas its induction by Gram-negative bacteria remains poorly defined. To address this gap, we aimed to determine whether heat-killed Klebsiella pneumoniae (HK Kp) induces trained immunity through metabolic and hematopoietic reprogramming to confer heterologous antibacterial protection.
METHODS: HK Kp-trained murine bone marrow-derived macrophages and HK Kp-immunized C57BL/6 mice were employed to interrogate functional, metabolic, and transcriptomic reprogramming in vitro, hematopoietic progenitor remodeling in vivo, and protective efficacy against systemic Salmonella Typhimurium and Staphylococcus aureus infection.
RESULTS: HK Kp-trained macrophages showed markedly enhanced IL-1β secretion across all restimulation conditions, stimulus-dependent amplification of TNF-α responses, increased phagocytosis, and improved intracellular control of S. typhimurium, together with sustained upregulation of the glycolytic enzymes-encoding genes Hk2 and Pfkfb3. Transcriptomic profiling revealed extensive reprogramming enriched in glycolysis/gluconeogenesis and hematopoietic cell lineage pathways. In vivo, HK Kp immunization shifted bone marrow stem/progenitor compartments toward a myeloid-biased state. HK Kp-trained mice challenged with lethal S. typhimurium or S. aureus exhibited less weight loss, improved survival rates, and reduced bacterial burdens.
CONCLUSIONS: Inactivated K. pneumoniae orchestrates metabolic and hematopoietic reprogramming to establish enhanced innate immune responsiveness and confer heterologous protection in murine S. typhimurium and S. aureus sepsis models, supporting its potential as a potent inducer of trained immunity. These findings establish HK Kp-based trained immunity as a promising strategy for combating multidrug-resistant and vaccine-evading pathogens.

Keywords:  Klebsiella pneumoniae; hematopoietic stem and progenitor cells; heterologous antibacterial protection; metabolic reprogramming; trained immunity

DOI:  https://doi.org/10.3390/vaccines14040300
Carbohydr Polym. 2026 Jul 01. pii: S0144-8617(26)00390-5. [Epub ahead of print]383 125273

Bletilla striata polysaccharide as a dual-hit biologic: Orchestrating pyroptosis inhibition and trained immunity for chronic wound resolution.

Yuwen Wang, Yufei Wang, Pinyi Tian, Yiyuan Zhang, Ke Cao, Shuonan Xie, Shiqiang Wang, Junfeng Niu.

  Chronic wounds, particularly diabetic foot ulcers (DFUs), represent a stalled inflammatory state driven by excessive NLRP3-mediated pyroptosis and defective innate immune memory. Bletilla striata polysaccharide (BSP), a neutral glucomannan from the orchid Bletilla striata, has emerged as a promising immunomodulatory candidate. This review critically examines the pharmacological potential of BSP, focusing on its structure-activity relationships (SAR)-specifically how extraction-dependent variations in molecular weight, mannose:glucose ratio, and degree of acetylation dictate receptor recognition. Emerging preclinical evidence suggests a "dual-hit" mechanism: BSP directly inhibits NLRP3 inflammasome assembly and gasdermin D-mediated pyroptosis to salvage tissue, while its degradation fragments induce epigenetic and metabolic reprogramming (trained immunity) in myeloid cells to prevent recurrence. Crucially, we discuss the "double-edged" nature of this immune training, weighing its benefits in antimicrobial defense against the theoretical risks of maladaptive systemic inflammation. We further analyze translational barriers, including the "quality-by-design" approaches needed to overcome batch variability and the regulatory pathway for botanical biologics. This review positions BSP not merely as a dressing, but as a sophisticated modulator of the pyroptosis-trained immunity axis, necessitating rigorous clinical validation to define its therapeutic window.

Keywords:  Biomaterials; Bletilla striata polysaccharide; Chronic wound healing; Glucomannan; Pyroptosis; Trained immunity

DOI:  https://doi.org/10.1016/j.carbpol.2026.125273
Curr Issues Mol Biol. 2026 Apr 21. pii: 426. [Epub ahead of print]48(4):

Microglial Innate Immune Memory: Implications and Research Advances in Central Nervous System Disorders.

Yaru Song, Shiyi Shu, Xiansi Zeng, Manli Xia, Junru Liu, Li Li.

  The central nervous system (CNS), comprising the brain and spinal cord, represents the core regulatory hub of the body. Damage to the CNS often leads to irreversible structural and functional impairments of neural tissues, posing a major global public health challenge. Immune memory encompasses two states: immune training and immune tolerance, which are characterized by enhanced or attenuated immune responses, respectively, following initial exposure to external stimuli in immune cells such as monocytes and macrophages. Microglia, the resident immune cells of the CNS, can be rapidly activated by external stimuli. Accumulating evidence indicates that microglial immune memory plays a critical role in sustaining states and neuroinflammatory responses in CNS disorders. Specifically, the immune training state promotes amyloid-β (Aβ) accumulation in the brains of Alzheimer's disease (AD) model mice, thereby exacerbating neuronal damage, whereas the immune tolerance state suppresses pro-inflammatory cytokine expression and alleviates neuroinflammation. This review focuses on two immune memory states in microglia-training and tolerance-and what triggers them. We summarize their roles and mechanisms in CNS diseases. Specifically, we break down how epigenetic and metabolic reprogramming control microglial immune memory, with an emphasis on how these two processes interact during memory formation and maintenance. Our goal is to fill key knowledge gaps about their combined effects and to suggest new therapeutic targets. Evidence shows that immune memory acts as a "double-edged sword" in the CNS: it can either fuel harmful inflammation and worsen damage, or, when moderately activated, protect nerves. Therefore, precisely balancing these two states could help reduce harmful inflammation while preserving the protective functions of microglia, offering a new, reversible immunotherapy for CNS diseases.

Keywords:  central nervous system; immune tolerance; immune training; microglia; signal pathway

DOI:  https://doi.org/10.3390/cimb48040426
Biochem Pharmacol. 2026 Apr 27. pii: S0006-2952(26)00343-6. [Epub ahead of print] 118010

Epigenetic reprogramming in tuberculosis: mechanisms of immune evasion and host-directed therapies.

Xinran Ding, Chenyan Zhou, Jiahai Shi, Yongwei Qin.

  Mycobacterium tuberculosis (Mtb) evades host immunity by actively reprogramming host gene expression, which allows the pathogen to persist within immune cells. Recent high-throughput sequencing and epigenomic studies have shown that Mtb reshapes the host epigenetic landscape by altering DNA methylation, histone modifications (including acetylation and methylation), and non-coding RNA networks. These modifications impact immune transcriptional programs and create an intracellular environment that favors bacterial survival. Importantly, these reversible epigenetic signatures offer promising pharmacological targets. This review systematically explores the immunological consequences of host epigenetic regulation during Mtb infection, evaluates the mechanisms of trained immunity, and highlights the therapeutic potential of pharmacological epigenetic modulators, such as inhibitors of histone deacetylases, DNA methyltransferases, and miRNA modulators. Furthermore, it discusses the development of emerging druggable targets, including novel epigenetic modifiers and immunometabolic hubs, while emphasizing the potential synergy of combining these epigenetic host-directed therapies with conventional antibiotics for treating tuberculosis.

Keywords:  Bacillus Calmette-Guérin-induced trained immunity; Emerging druggable target; Epigenetic therapeutics; Host-directed therapy; Immunometabolism; Mycobacterium tuberculosis

DOI:  https://doi.org/10.1016/j.bcp.2026.118010
Front Immunol. 2026 ;17 1818835

Immuno-inflammatory-metabolic interactions in cardiovascular diseases: a review from basic mechanisms to clinical translation.

Xingshun Zhu, Fengmei Zhang, Yuxin Wei, Yan Zhao, Jiawei Guo.

  Cardiovascular disease (CVD) remains the leading cause of mortality and disability worldwide, imposing a substantial burden on individuals, families, and healthcare systems. Despite major advances in controlling conventional risk factors (e.g., blood pressure, glycaemia, and lipids), a considerable residual risk persists, highlighting the need to elucidate additional pathogenic mechanisms and to develop more effective preventive and therapeutic strategies. Accumulating experimental and clinical evidence indicates that immune dysregulation and chronic low-grade inflammation are not merely associated with CVD but actively drive disease progression-from lesion initiation to acute thrombotic events. These processes are further shaped by metabolic status, lifestyle factors, psychosocial stress, and environmental exposures, and age-related genetic immune changes such as clonal hematopoiesis of indeterminate potential (CHIP). Atherosclerosis, the predominant pathological substrate of most CVDs, is now widely recognized as a chronic immune-inflammatory disease. Emerging concepts including immunometabolic reprogramming, trained immunity(distinguished by central and peripheral subtypes), the thrombo-inflammatory axis, and allostatic load provide an integrative framework for understanding CVD as a systemic disorder. Here, we synthesize recent advances in innate and adaptive immune mechanisms, immunometabolic dysregulation, and inflammation-thrombosis crosstalk that collectively govern plaque formation, destabilization, and clinical events. We also discuss how lifestyle-related factors (e.g., diet, fasting, physical activity, and stress) may modulate long-term cardiovascular risk through trained immunity and inflammatory pathways, and we highlight progress in immune biomarkers and anti-inflammatory interventions, and the immunometabolic effects of modern cardiometabolic drugs (GLP-1 receptor agonists, SGLT2 inhibitors). Additionally, we elaborate on the translational potential of short chain fatty acid derivatives in reversing innate immune inflammatory memory, and clarify the distinct cardiovascular toxic mechanisms of immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) therapy in cardio-oncology. Conceptualizing CVD as a systemic immune-metabolic-inflammatory disease may facilitate improved risk stratification and inform precision prevention and treatment strategies.

Keywords:  Allostatic load; cardiovascular disease; immune inflammation; lifestyle intervention; metabolic reprogramming; thrombo-inflammation; trained immunity

DOI:  https://doi.org/10.3389/fimmu.2026.1818835
Immunol Lett. 2026 Apr 27. pii: S0165-2478(26)00053-2. [Epub ahead of print] 107180

RanGAP1 plays a vital role in anti-infective functions of macrophages and sepsis progression.

Linlin Mao, Genming Liu, Jiahuan Zhang, Qiongzhi Zhao, Xinyi Zhang, Sheng Zhang, Yue Zhang, Xiaochun Bai.

  Ran GTPase-activating protein 1 (RanGAP1) is a known regulator of nucleocytoplasmic transport; however, its specific function within innate immunity remains undefined. Here, we show that low RanGAP1 expression correlates with poor survival outcomes in septic patients and demonstrate that RanGAP1 expression and subcellular localization are dynamically regulated in macrophages following lipopolysaccharide (LPS) stimulation. We observed that deletion of RanGAP1 in macrophages exacerbates sepsis progression by using a cecal ligation and puncture (CLP) murine model. Mechanistically, RanGAP1 deficiency significantly impairs macrophage anti-infective functions, including inflammatory cytokine production, pathogen clearance, and antigen processing. These findings highlight RanGAP1 as a central regulator of macrophage immune responses, suggesting that its activity is a critical determinant of septic outcomes.

Keywords:  RanGAP1; anti-infection; lipopolysaccharide; macrophage; sepsis

DOI:  https://doi.org/10.1016/j.imlet.2026.107180
Fish Shellfish Immunol. 2026 Apr 27. pii: S1050-4648(26)00293-7. [Epub ahead of print] 111389

Transcriptome analysis revealed immune protection conferred by bath vaccination with formalin-killed Vibrio parahaemolyticus on Penaeus vannamei.

Ma Ramela Angela Bermeo-Capunong, John Paul Matthew Domingo Guzman, Garner Algo Langote Alolod, Reiko Nozaki, Jumroensri Thawonsuwan, Keiichiro Koiwai, Hidehiro Kondo, Ikuo Hirono.

  Acute hepatopancreatic necrosis disease (AHPND) remains a challenge in shrimp aquaculture. Growing interest in the adaptive-like immunity of crustaceans has raised prospects for vaccination strategies. In this study, we utilized formalin-killed Vibrio parahaemolyticus (FKC-Vp) strains (TUMSAT_N3, TUMSAT_FP11, and TUMSAT_D6) as vaccine administered via bath vaccination in Penaeus vannamei shrimp. The FKC-Vp strains and efficient bath conditions were initially optimized. Shrimps were immersed for either 1 h or 2 h at 1% or 2% FKC concentration and then transferred to new tanks for subsequent observation. Among which, shrimps bathed with 1% FKC-VpFP11 for 1 h showed higher survival rate and upregulated expression of immune-related genes without histopathological damage in the hepatopancreas. Based on these optimal conditions, RNA sequencing via Illumina platform was then performed on hepatopancreas and stomach tissues collected at 24 h post-vaccination (pv). Transcriptomic profile revealed differentially expressed genes (DEGs), where GO and KEGG analyses further identified enriched metabolic, stress response, and bacterial mitigation signaling pathways. Twelve significant immune-related DEGs involved in pathogen recognition, antimicrobial defense, ROS elimination, and epigenetic modulation were further validated via qPCR. These DEGs were examined at 24 h and 7 d pv, and 24 h post-challenge (pc). Results showed temporal expression shift from an acute-phase response at 24 h pv, to a primed state at 7 d pv, followed by an activated defense state at 24 h pc. Notably, antimicrobial effectors (GILT, hemocyanin C-chain) peaked at 24 h pv, while recognition factors (C-type lectin, perlucin) and putative epigenetic regulators (zinc finger, E3 ubiquitin ligase, late histone H1) remained sustained or upregulated through 7 d pv. A significant interaction between time and vaccinated treatment was observed in GILT. Despite the VpAHPND challenge occurring 7 d pv, all DEGs were upregulated at 24 h pc, with significant elevated expression in hemocyanin C-chain. This correlated with increased survival rate (80%) in the vaccinated shrimp compared to the control. Our findings provide a molecular basis for immune priming induced by 1% FKC-VpFP11, suggesting a memory-like mechanism that warrants further investigation. Overall, this study emphasized a cost-effective and protective disease-control strategy for P. vannamei against VpAHPND.

Keywords:  AHPND; Penaeus vannamei; immune priming; trained immunity; transcriptome analysis

DOI:  https://doi.org/10.1016/j.fsi.2026.111389
Nat Rev Drug Discov. 2026 Apr 28.

IL-2-TGFβ co-agonist induces immune tolerance.

Sarah Crunkhorn.

DOI: https://doi.org/10.1038/d41573-026-00073-x
J Adv Res. 2026 Apr 26. pii: S2090-1232(26)00368-1. [Epub ahead of print]

Chac1 deficiency confers sepsis resistance by enriching gut microbiota-derived indole-3-carboxylic acid to drive macrophage metabolic shifts.

Jing-Juan Hu, Si-Yuan Feng, Ling Wu, Shi-Ying He, Xiao-Feng Chen, Ge-Hui Li, Yue Min, Hong-Ling Xu, Qi-Shun Sun, Sun Xie, Jian-Liu, Feng Chen, Ke-Xuan Liu, Fan Deng.

   INTRODUCTION: Sepsis is a life-threatening dysregulated host response to infection, lacks effective therapies. ChaC glutathione-specific γ-glutamylcyclotransferase 1 (CHAC1) is elevated in sepsis and correlates with severity, but its functional role in the pathogenesis of sepsis-induced organ damage is unclear.
OBJECTIVES: We aimed to define the contribution of CHAC1 to sepsis-induced organ injury and elucidate the underlying mechanisms involving gut microbiota-derived metabolites and host immunity.
METHODS: Chac1-/- mice were subjected to LPS-induced endotoxemia to evaluate organ injury. The gut microbiota's role was defined by 16S rRNA gene sequencing, microbiota depletion and fecal microbiota transplantation (FMT). The effect of microbiota-derived metabolite indole-3-carboxylic acid (ICA) was assessed in vivo. Underlying mechanisms were investigated via macrophage depletion, AHR pharmacological/genetic inhibition, and in vitro studies with RAW264.7 cells and bone marrow-derived macrophages.
RESULTS: Serum CHAC1 was elevated in septic patients and mice, correlating with disease severity. Chac1 deficiency protected against sepsis-induced multi-organ injury, an effect that was gut microbiota-dependent. Chac1-/- mice exhibited a remodeled gut microbiota, with enrichment of Akkermansia muciniphila and increased levels of the tryptophan metabolite ICA. Exogenous ICA or A. muciniphila supplementation recapitulated the protective phenotype. ICA treatment improved survival, attenuated inflammation, and reduced organ injury by activating the aryl hydrocarbon receptor (AHR) in macrophages. This was evidenced by AHR nuclear translocation, and siRNA-mediated AHR knockdown abolished ICA's effects. ICA reprogrammed macrophage metabolism, inhibiting glycolysis (reduced lactate) and enhancing oxidative phosphorylation (increased ATP, oxygen consumption rate), leading to suppressed pro-inflammatory responses.
CONCLUSION: Chac1 deficiency confers sepsis resistance by enriching protective gut microbiota and elevating ICA, which acts as a major downstream effector. ICA activates the AHR in macrophages, driving a metabolic shift from glycolysis to oxidative phosphorylation that dampens inflammation and organ injury. This CHAC1-microbiota-ICA-AHR-macrophage axis identifies ICA as a promising therapeutic candidate and CHAC1 as a potential prognostic biomarker for sepsis.

Keywords:  CHAC1; Indole-3-carboxylic acid; Macrophage; Metabolic reprogramming; Sepsis

DOI:  https://doi.org/10.1016/j.jare.2026.04.065
Cell Immunol. 2026 Apr 26. pii: S0008-8749(26)00051-1. [Epub ahead of print]425 105111

MPC1 regulates endotoxin tolerance of macrophages through mitochondrial oxidative stress resistance.

Yan Liu, Feng Qi, Hongrui Zeng, Dandan Huang, Wenfeng Zhang, Yifan Zhang, Jianping Gong, Lunjian Xiang, Zhujun Yi.

  Increasing evidence highlights the crucial role of endotoxin tolerance in the regulation of the sepsis, yet its underlying mechanisms remain poorly understood. Here, we provide evidence to support a novel role for the mitochondrial pyruvate carrier1 (MPC1)-mediated mitochondrial oxidative stress resistance in regulation of endotoxin tolerance in macrophages. We observed decrease expression of MPC1 in macrophages of sepsis models both in vitro and in vivo, while LPS-tolerant macrophages exhibited increased MPC1 levels. Overexpression of MPC1 significantly reduced LPS-induced inflammatory responses and oxidative stress, suggesting its anti-inflammatory properties. Intriguingly, we found that overexpression of MPC1 did not foster endotoxin tolerance in macrophages. Furthermore, Overexpression of MPC1 inhibited mitochondrial oxidative stress resistance mediated by mitochondrial reactive oxygen species (mtROS), which weakened the resistance of macrophages to LPS secondary stimulation, and then inhibited endotoxin tolerance. Despite mtROS typically acting as pro-inflammatory mediators, our findings indicate that mtROS which regulated via the SIRT3/SOD2 pathway, is essential for MPC1's control over mitochondrial oxidative stress resistance and endotoxin tolerance. Collectively, these findings uncover a novel mechanism through which MPC1 modulates inflammation and induces endotoxin tolerance, underscoring the potential of targeting MPC1 in sepsis treatment.

Keywords:  Endotoxin tolerance; Mitochondrial oxidative stress resistance; Mitochondrial pyruvate carrier 1; SIRT3/SOD2 pathway; Sepsis

DOI:  https://doi.org/10.1016/j.cellimm.2026.105111
PLoS Pathog. 2026 Apr 30. 22(4): e1014192

BRD4 modulates antimicrobial defense via non-canonical NRF2 activation in macrophages to confer protection against sepsis.

Jinfeng Hu, Xuming Gao, Guo Li, Xiaoxin He, Yanting Ke, Zhongheng Zhang, Duozhi Pang, Zhen Lin, Cailian Xie, Xiaoting Chen, Minting Jiang, Shuping Zheng, Suhong Yu, Mingrui Lin, Dun Pan, Xiaopei Shen, Xiangming Hu.

Sepsis is a life-threatening condition characterized by dysregulated immune responses and high mortality, driven by persistent pathogens and compromised antimicrobial defenses. We identify BRD4, an epigenetic regulator, as a crucial modulator of macrophage antimicrobial function and survival in sepsis. Sepsis significantly reduces BRD4 expression in monocytes/macrophages in both human patients and murine models, with decreased BRD4 levels correlating with disease severity. Myeloid-specific deletion of Brd4 exacerbates mortality by impairing macrophage phagocytosis and bactericidal activity. BRD4 interacts with NRF2, disrupting the NRF2-KEAP1 complex, which enhances NRF2 stability and nuclear translocation, leading to the upregulation of scavenger receptors essential for bacterial clearance. Notably, restoration or activation of NRF2 rescues the macrophage functional defects induced by Brd4 deficiency both in vitro and in vivo, highlighting the therapeutic potential of this pathway. Our findings reveal that BRD4 downregulation in human sepsis predicts disease severity, presenting BRD4 as both a biomarker and a therapeutic target. The BRD4-NRF2 axis offers a novel approach to restoring host defense and improving sepsis treatment strategies.

DOI: https://doi.org/10.1371/journal.ppat.1014192
J Clin Invest. 2026 May 01. pii: e195001. [Epub ahead of print]136(9):

Secreted phospholipase PLA2G5 acts as a hemolytic factor in sepsis.

Michihiro Takahama, Krysta S Wolfe, Gabriella Richey, Madison Plaster, Anna Czapar, Fabian Hernandez, Denis Cipurko, Tatsuki Ueda, Yoshimi Miki, Yuki Nagasaki, Yoshitaka Taketomi, Tatsuya Saitoh, Tadafumi Kawamoto, Steven M Dudek, Makoto Murakami, Nicolas Chevrier.

  Sepsis is a systemic response to infection with life-threatening consequences such as hemolysis, a predictor of mortality risks for the disease. Here, by measuring organism-wide changes in gene expression, we discovered that the secreted phospholipase PLA2G5 is induced in colon cell types during sepsis. The genetic deletion of Pla2g5 and treatment with a PLA2G5 antibody were both associated with protection from lethal sepsis. Treatment with a PLA2G5 antibody during sepsis was associated with increased splenic red pulp macrophages and improved iron homeostasis, linking PLA2G5 to red blood cell homeostasis during sepsis. Mechanistically, bloodborne PLA2G5 led to intravascular hemolysis through its lipolytic activity on red blood cell membranes. In humans with sepsis due to bacterial, fungal, or viral infections, the serum level of PLA2G5 was elevated and predictive of disease severity and mortality. We conclude that sepsis corrupts PLA2G5 into becoming an intravascular hemolytic factor which is toxic for host red blood cells.

Keywords:  Bacterial infections; Biomarkers; Expression profiling; Infectious disease; Inflammation

DOI:  https://doi.org/10.1172/JCI195001
Sci Adv. 2026 May;12(18): eaed1676

d-amino acids restrain macrophage IL-1β release through gasdermin D acetylation.

Zebiao Wu, Qilin Hu, Yinhao Shen, Jian Fu, Bingnan Liu, Meimei Zhang, Ifen Hung, Chunxue Liu, Wenkai Ren.

d-amino acids have been detected in various tissues; however, whether d-amino acids shape immune cell (e.g., macrophages) function remains undefined. Here, we demonstrated that inflammatory macrophages decrease mRNA expression of d-amino acid oxidase (DAAO) and d-aspartate oxidase (DDO) through nuclear factor κB (NF-κB) signaling. Notably, inhibition of DAAO or DDO increases the concentration of intracellular d-amino acids, consequently suppressing IL-1β release. Mechanistically, d-amino acids inhibit the formation of gasdermin D (GSDMD) oligomer via GSDMD-K146 acetylation. d-amino acids directly bind and increase the enzyme activity of mitochondrial pyruvate dehydrogenase (PDH), resulting in acetyl-coenzyme A production for acetylation. Consistently, d-Ala/d-Glu supplementation or myeloid-specific deletion of DDO attenuates lipopolysaccharides (LPS)-induced sepsis in mice. Collectively, our study reveals a mechanism involving acetylation mediated by d-amino acids in regulation of macrophage function, providing a potential therapeutic strategy for treating macrophage-associated inflammatory diseases.

DOI: https://doi.org/10.1126/sciadv.aed1676
Immun Inflamm. 2026 ;2(1): 22

Toll-like receptors in innate immunity and inflammation: from fundamental biology to clinic insights.

Cheng Qian, Xuetao Cao, Jules A Hoffmann.

  The discovery and investigation of Toll-like receptors (TLRs) has fundamentally reshaped our understanding of innate immunity and inflammation over the past four decades. These pivotal pattern-recognition receptors play a canonical role as sentinels that detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). In addition, TLR signaling is subject to exquisite multilayered regulation to prevent excessive inflammation and maintain immune homeostasis. Such regulation includes posttranslational modifications, epigenetic reprogramming, metabolic rewiring, and dynamic assembly of signaling condensates. This review comprehensively summarizes the intrinsic regulatory networks and tissue-microenvironment crosstalk that fine-tune TLR responses. We highlight the central roles of TLR signaling in infection, autoimmunity, cancer, inflammaging, cardiovascular diseases, and neurodegenerative disorders, underscoring how dysregulation drives pathology. Finally, we examine recent analyses and future prospects for pharmacological modulation of TLR pathways with agonists or antagonists as a promising therapeutic strategy for a broad spectrum of inflammatory and immune-mediated diseases. By bridging foundational mechanisms with clinical insights, this article illustrates how TLR research continues to illuminate immune regulation and offers novel avenues for targeted immunotherapy.

Keywords:  Immune disorders; Immune regulation; Immunotherapy; Inflammation; Innate signaling; Toll-like receptors

DOI:  https://doi.org/10.1007/s44466-026-00040-6
Methods Cell Biol. 2026 ;pii: S0091-679X(26)00087-7. [Epub ahead of print]206 109-122

Measurement and quantification of macrophage lytic cell death by kinetic microscopy.

Sara Cahill, Fiachra Humphries.

  Macrophages are innate immune cells that are critical in the maintenance of tissue homeostasis and defense against pathogens. Programmed cell death is a critical tool macrophages use to clear pathogens and to alert surrounding cells to damage following induction of cell death. Diverse forms of cell death, including pyroptosis, necroptosis, ferroptosis, and secondary apoptosis following apoptosis, result in loss of plasma membrane integrity. Membrane disruption occurs following the oligomerization of pore-forming proteins into the cell membrane, releasing cytokines and damage associated molecular patterns that trigger the immune response. Thus, quantification of cell membrane permeability is an effective method for assessing cell death in macrophages. Many different factors, including macrophage polarization, stimulation, and inflammatory state, can impact macrophage predisposition to, and rate of, programmed cell death. Thus, it is important to have a method of accurately assessing macrophage cell death kinetically, rather than at a single endpoint. In this protocol, we describe a protocol for assessing cell death in macrophages by quantifying cell membrane permeability using kinetic microscopy. This method overcomes limitations of common single time point metrics for assessing cell death and is adaptable and scalable for use in assessing cell death across different cell types and treatment conditions.

Keywords:  Kinetic microscopy; Lytic; Macrophage; Pyroptosis

DOI:  https://doi.org/10.1016/bs.mcb.2026.02.019
Nat Commun. 2026 Apr 25.

RPSA-OLFM4 axis governs neutrophil migration against bacterial infection and sepsis.

Tong Wu, Xiangrui Yang, Siyu Lei, Shaopeng Wei, Wei Wang, Yi Sun, Hexiang Jiang, Xiuwen Jia, Yanyan Tian, Kaixin Zhang, Yufan Zhang, Haizhen Chen, Jing Huang, Fengyang Li, Na Li, Liancheng Lei.

Neutrophil migration to bacterial infection sites is key for host defense. Host ribosomal protein SA (RPSA) has been recently reported to regulate the anti-infection immunity of immune cells; however, its role in neutrophil migration remains unclear. Here, using myeloid-specific Rpsa-deficient mice, we found that RPSA deletion inhibited neutrophil infiltration and markedly exacerbated Streptococcus suis serotype 2 infection. Adoptive cell transfer and neutrophil depletion assays identified RPSA as vital for the anti-infective function of neutrophils. Mechanistically, RPSA deficiency induced the overexpression of olfactomedin 4 (OLFM4), which in turn inhibited the activation of the RhoA/ROCK1/pMLC2 signaling pathway, reduced MYH9 expression, and caused aberrant MYH9 translocation from the uropod to the cytosol in migrating neutrophils. Ultimately, this disrupted cytoskeletal polarization and uropod extension, thereby abrogating migratory function. Clinically, septic patients' neutrophils exhibited reduced RPSA and elevated OLFM4 expression, a phenotype that correlated with a marked impairment of migratory capacity. Therapeutic targeting of the RPSA-OLFM4 axis restored neutrophil migration and improved disease outcomes in both S. suis 2-infected and septic mice. Thus, our findings demonstrate that RPSA promotes neutrophil migration via downregulating OLFM4 to counter bacterial infection, and establish the RPSA-OLFM4 axis as a critical immune migratory checkpoint in host antibacterial immunity.

DOI: https://doi.org/10.1038/s41467-026-72365-0
Nat Commun. 2026 Apr 30.

A Muribaculaceae-enriched microbiota exacerbates TLR4-dependent Acinetobacter baumannii-induced hyperinflammatory sepsis.

Seonghan Jang, Yu-Jeong Kim, Jisun Park, Dajeong Kim, Tae-Hwan Kim, Soohyun Lee, Doo-Jin Kim, Choong-Min Ryu, Hwi Won Seo.

Host survival during sepsis depends not only on pathogen burden but also on inflammatory thresholds calibrated by the gut microbiota. Here, we show that different survival outcomes were observed in genetically equivalent female C57BL/6 mouse populations depending on their specific gut microbiota configuration. A Muribaculaceae-enriched gut microbiota, characterized by the dominance of Sangeribacter muris KT1-3, predisposed mice to fatal sepsis caused by Acinetobacter baumannii via TLR4-dependent hyperinflammation. This lethal phenotype, reproduced by colonization with S. muris strain KT1-3, was transferable by fecal microbiota transplantation and co-housing. Notably, fixed-dose LPS challenge and ex vivo stimulation assays demonstrated that this configuration induces a heightened TLR4-dependent inflammatory responsiveness independent of bacterial replication. Single-cell transcriptomics revealed that these microbiota-derived factors establish a transcriptionally pre-activated macrophage state, resulting in production of excessive pro-inflammatory cytokines upon challenge. Mechanistically, S. muris strain KT1-3 releases heat-stable and low-molecular-weight (<3 kDa) metabolites that are sufficient to potentiate systemic cytokine surges under a fixed-dose endotoxin challenge in vivo, effectively lowering the host's activation threshold for TLR4-driven signaling. Tlr4-deficient mice harboring the KT1-3-enriched susceptible microbiota survived despite persistent bacterial dissemination, demonstrating that the microbiota-TLR4 axis dictates hyperinflammatory A. baumannii-induced sepsis outcomes by modulating inflammatory magnitude rather than pathogen clearance. Our results provide a conceptual framework for how specific gut microbiota configurations modulate host susceptibility and drive infection resilience.

DOI: https://doi.org/10.1038/s41467-026-72435-3
FEBS Open Bio. 2026 Apr 26.

Lipopolysaccharide uptake is augmented in lipopolysaccharide-tolerant mouse macrophage-like cells via increased CD14 expression.

Saeka Nishihara, Takayuki Manabe, Mika Jouta, Kiyoshi Kawasaki.

  Lipopolysaccharide (LPS) tolerance can be recognized as a modulation of innate immune responses rather than merely a hyporesponsiveness to LPS, with CD14 being crucial for both LPS uptake and LPS signaling. In this study, we observed that LPS-tolerant mouse macrophage-like cells, in which LPS-induced TNF-α and IFN-β production was suppressed, exhibited a dramatic increase in surface CD14 expression. Also, we found that LPS uptake was enhanced in LPS-tolerant mouse macrophage-like cells, but not when treated with an anti-CD14 antibody. While previous studies have reported increased CD14 expression and enhanced LPS uptake in LPS-tolerant cells, our findings reveal that overexpressed CD14 in LPS-tolerant mouse macrophage-like cells is responsible for the enhanced LPS uptake in these cells.

Keywords:  LPS hyporesponsiveness; glycosylphosphatidylinositol‐anchored CD14; innate immunity

DOI:  https://doi.org/10.1002/2211-5463.70261