bims-traimu 2026-02-08 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2026–02–08
nine papers selected by
Yantong Wan, Southern Medical University

A pathogen peptidoglycan scaffold coated with artificial biomembrane promotes broad resistance to bacterial infections by dynamically reprogramming macrophage metabolism.
Evaluating the non-specific effects of BCG vaccination on the immune system and serological response to influenza vaccination in the elderly: A randomised controlled trial.
Trained Immunity Empowers Vaccine Design and Application.
Microglial epigenetic memory is associated with accelerated resolution of inflammatory pain induced by prophylactic macrophage-derived small extracellular vesicles.
Aerobic glycolysis promotes NLRP3 inflammasome activation via NLRP3 lactylation.
Ketogenic diet alleviates septic lung injury via microbial gut-lung axis.
Unveiling a novel function of Aconitase-2: attenuating lung ischemia-reperfusion injury via inhibition of pulmonary endothelial apoptosis.
FGF 13 functions as a regulator of the ERK/aerobic glycolysis axis in the inflammatory state during septic lung injury.
Acute peritonitis-induced adipose CD127+ ILC1s express PD-L1 and ameliorate inflammation in mice.

Mater Today Bio. 2025 Dec;35 102266

A pathogen peptidoglycan scaffold coated with artificial biomembrane promotes broad resistance to bacterial infections by dynamically reprogramming macrophage metabolism.

Junjie Guo, Shuo Jia, Zibo Mai, Chaonan Wang, Zheng Jia, Jiaqing Wang, Xinran Yao, Jiaqi Liu, Fang Wang, Junwei Ge.

  The increasing severity of multidrug-resistant (MDR) bacteria and the shortage of effective treatment strategies urgently require the development of new immunotherapies to combat superbug infections. Trained immunity may offer a novel and effective mechanism to combat resistant superbugs. However, there are currently few materials capable of effectively activating trained immunity, highlighting the need for new agents that provide more durable protection. In this study, we developed a bacterium-like particle (BLP) based on protein-free artificial biomembrane coating immune activator, named LM@pBLP, which features a simple and rapid preparation process, excellent biocompatibility, long-term stability, and a cost-effective advantage. LM@pBLP trains the immune system to target a broad range of pathogens, offering rapid, broad-spectrum, and long-lasting protection against MDR infections. After stimulation with LM@pBLP, it activates glutathione metabolism and amino acid metabolism, induces macrophage metabolic and epigenetic reprogramming changes, and regulates phagocytosis and inflammatory responses to infection. Additionally, LM@pBLP regulates reactive oxygen species (ROS), thereby maintaining oxidative stress homeostasis. Our study demonstrates that LM@pBLP primarily provides rapid, broad-spectrum, and long-lasting protection for experimental animals by activating trained immunity, which opens a new avenue for addressing MDR infections.

Keywords:  Artificial biomembrane coating; Immune modulation; MRSA; Metabolic reprogramming; Trained immunity

DOI:  https://doi.org/10.1016/j.mtbio.2025.102266
Vaccine. 2026 Feb 05. pii: S0264-410X(26)00113-1. [Epub ahead of print]76 128305

Evaluating the non-specific effects of BCG vaccination on the immune system and serological response to influenza vaccination in the elderly: A randomised controlled trial.

Anne Marie Rosendahl Madsen, Frederik Schaltz-Buchholzer, Ramona Trebbien, Rutger Roring, Nina Bang, Christian Nielsen, Mette Bliddal, Lene Annette Norberg, Mihai G Netea, Torben Barington, Peter Aaby, Sören Möller, Christine Stabell Benn.

   OBJECTIVES: The Bacillus Calmette-Guerin (BCG) vaccine has beneficial effects on the immune system, which may lead to non-specific protection against non-tuberculous infections and increase the response to subsequent vaccinations. Seasonal influenza vaccination is used to protect senior citizens against influenza, but the serological response to the inactivated influenza vaccine (IIV) decreases in the elderly due to immunosenescence. The aim of this study was to test the capacity of BCG to boost the specific immune response to IIV and explore the effect of BCG on the innate immune system and health of senior citizens.
METHODS: A randomised controlled trial with a nested immunological study including 273 Danish citizens >65 years. Participants were randomised into four equally sized groups combining BCG with IIV in different sequences compared with IIV alone. The primary outcome was change in influenza antibody hemagglutination inhibition (HI) titre four weeks after vaccination. Secondary outcomes were infection rate during six months follow-up, and association between influenza antibody titre and infection rate. In subgroup analyses, we explored the effect of BCG on lymphocyte populations seven days after IIV and on cytokine production after stimulation of mononuclear cells in vitro.
RESULTS: Four weeks after influenza vaccination, the mean fold change in HI titre over all serotypes was 2.3-2.5 with no significant differences between the treatment groups. Seroconversion rate was comparable between treatment groups, and in strata of age and sex. There was no difference in the rate of infection between the groups and there was no association with influenza antibody level. We found no difference in distribution of lymphocytes. Combining BCG with IIV had modest impact on in vitro cytokine production compared with IIV alone.
CONCLUSION: BCG vaccination did not increase serological response to seasonal influenza vaccination or reduce the incidence of infection in this population of Danish senior citizens.
TRIAL REGISTRATION: EU Clinical Trials Register (EudraCT number 2019-002781-12).
SUMMARY: In this randomised clinical trial of Danish senior citizens, BCG vaccination did not influence serological response to influenza vaccination or reduce the risk of infection compared with placebo. There was no clear indication of induction of trained immunity.

Keywords:  BCG vaccine; Immunosenescence; Influenza antibody; Non-specific vaccine effects; Randomised controlled trial; Trained immunity

DOI:  https://doi.org/10.1016/j.vaccine.2026.128305
ACS Infect Dis. 2026 Feb 07.

Trained Immunity Empowers Vaccine Design and Application.

Qijun Hu, Zibo Mai, Bosen Wang, Ning Sun, Wenjuan Zhu, Jiaqing Wang, Junwei Ge, Mingchun Gao.

  The COVID-19 pandemic has exposed the limitations of traditional vaccine development models: these approaches rely excessively on pathogen-specific antigen design, feature lengthy development cycles, and struggle to address threats from rapidly mutating pathogens and emerging pathogens. Even before the pandemic, certain traditional vaccines (such as BCG) demonstrated "cross-protection" effects beyond their target diseases. The trained immunity (TRIM) theory offers a promising path to develop broad-spectrum, effective, and durable vaccines. This review summarizes core advances in TRIM within vaccinology, systematically outlining vaccine design strategies based on this concept for the first time. These strategies encompass vaccine-mediated cross-protection, methods to enhance vaccine potency and persistence, pathways to achieve broad-spectrum effects, and regulatory characteristics involving immune recognition, antigen delivery, safety, and tolerability. This study explores the synergistic effects and application prospects of TRIM adjuvants such as β-glucan and Toll-like receptor (TLR) agonists. The impact of transgenerational immune effects on offspring immune function provides a crucial direction for future research. It also highlights current limitations in studies regarding persistence, individual variability, and risks of excessive inflammation. Existing vaccines capable of inducing TRIM will inspire next-generation vaccine development. Innovative applications of this vaccine category can propel the advancement of trained immunity-based vaccines (TIbVs). This review proposes an innovative approach─the "Vaccine Immunity Foundation Hypothesis." This lays the groundwork for designing next-generation vaccines and advancing the clinical translation of TRIM therapies, establishing a theoretical foundation for developing broad-spectrum, highly effective, durable, and safe immune protection strategies.

Keywords:  heterologous protection; trained immunity; trained immunity-based vaccines; transgenerational effects; vaccine adjuvants; vaccine immunity foundation hypothesis

DOI:  https://doi.org/10.1021/acsinfecdis.5c00840
bioRxiv. 2026 Jan 16. pii: 2026.01.15.699551. [Epub ahead of print]

Microglial epigenetic memory is associated with accelerated resolution of inflammatory pain induced by prophylactic macrophage-derived small extracellular vesicles.

Xuan Luo, Jason R Wickman, Jason T DaCunza, Yuzhen Tian, Ahmet Sacan, Seena K Ajit.

Small extracellular vesicles (sEVs) including exosomes play an important role in intercellular communication and can exert immunomodulatory effects in recipient cells. We have shown that a single prophylactic intrathecal injection of sEVs from RAW 264.7 macrophages two weeks prior, promotes faster resolution of mechanical and thermal hypersensitivity in the complete Freund's adjuvant (CFA) mouse model of inflammatory pain. How this long-term memory develops, and how sEVs regulate immune responses are unknown. Recent studies have shown that priming microglia with inflammatory stimuli can enhance or suppress responses to a delayed secondary insult via epigenetic modifications. We hypothesized that prophylactic intrathecal administration of macrophage-derived sEVs confers accelerated resolution of inflammatory pain by reprogramming epigenetic memory in spinal microglia in recipient CFA model mice. To determine whether prophylactic sEVs could attenuate pain in the absence of microglia when administering sEVs, we ablated microglia using a colony-stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622. sEV-induced pain prophylaxis was completely abolished in PLX5622-fed mice, indicating that microglia are required to be present during sEV administration to confer early resolution of inflammatory pain hypersensitivity. ChIP-seq analysis in spinal microglia 14 days after sEV administration (prior to CFA) revealed an increased number of gene loci enriched for H3K4me1, a hallmark of innate immune memory. Furthermore, inhibiting the H3K4 mono-methyltransferase SETD7 abolished sEV-induced pain attenuation. Our findings indicate that both microglia and its epigenetic reprogramming contribute to pain prophylaxis induced by macrophage-derived sEVs, providing novel insights into the development of non-addictive preventive analgesia.

DOI: https://doi.org/10.64898/2026.01.15.699551
Cell Chem Biol. 2026 Feb 04. pii: S2451-9456(26)00023-1. [Epub ahead of print]

Aerobic glycolysis promotes NLRP3 inflammasome activation via NLRP3 lactylation.

Wei Liu, Tianyi Zhang, Bohong Wang, Hang Yin.

  Bacteria-infected macrophages undergo pyroptosis to release inflammatory cytokines, which contributes to host defense. It has been known that activated macrophages involve metabolic reprogramming. However, the metabolic changes and the role of metabolites in pyroptotic macrophages are not fully understood. Here, we revealed that aerobic glycolysis product, lactate, could promote NLRP3 inflammasome activation induced pyroptosis. We found that endogenous lactate facilitates ASC recruitment to NLRP3 cores on the organelle membrane, thus inducing NLRP3 inflammasome complex formation. Mechanistically, we identified NLRP3 as a target protein modified by lactate, which is lactylated by AARS2. We confirmed lactylated sites on NLRP3 by LC-MS/MS analysis and verified that lactylation at K24 and K565 of NLRP3 facilitates inflammasome activation in macrophage. In vivo, inhibition of lactate production alleviates inflammatory responses in polymicrobial sepsis. Overall, our results indicate the role of lactate in regulating macrophage pyroptosis and the crosstalk between metabolism and innate immunity.

Keywords:  NLRP3 inflammasome; lactylation; pyroptosis

DOI:  https://doi.org/10.1016/j.chembiol.2026.01.003
Cell Metab. 2026 Feb 04. pii: S1550-4131(26)00005-7. [Epub ahead of print]

Ketogenic diet alleviates septic lung injury via microbial gut-lung axis.

Mingyuan Wei, Xinzhu Yi, Zhuandi Lin, Jingjing Cai, Shanze Chen, Fang Zhou, Hanqin Cai, Xinfeng Lu, Juan Tang, Yunfeng Shi, Liping Cui, Lei Yang, Xinru Jing, Yunong Zeng, Rong Wu, Tingting Shu, Yuanyuan Li, Fangyuan Yang, Yi He, Zhibin Zhao, Yuqiong Yang, Wenjiao Zhu, Qiong Jiang, Weiwei Zhang, Xiang Tan, Zhuo Ma, Xiaoying Fan, Wei Ma, Sheng Li, Wensheng Shu, Hong Wei, Zhiming Xiang, Jack A Gilbert, Shenhai Gong, Zhang Wang.

  Sepsis is characterized by impaired immunity to infection, leading to multi-organ dysfunction, with the lung being the most vulnerable organ. Here, we show that ketogenic diet (KD) alleviates sepsis-induced lung injury through a microbial-gut-lung axis. KD alters the gut microbiota in mice and humans, enriching Limosilactobacillus reuteri and Lactiplantibacillus plantarum. Specific strains of these species produce a flavin-dependent monooxygenase (FMO) that converts oleic acid in KD into azelaic acid (AZA). During sepsis, AZA translocates to the lung, where it promotes neutrophil apoptosis and expands MerTK+ alveolar macrophages (AMs) via PPAR-γ activation, enhancing efferocytosis and resolution of lung injury. In patients with sepsis, elevated AZA correlates with improved clinical outcomes, including survival rates, ventilation-free days (VFDs), and pulmonary function, along with increased MerTK+ AMs and apoptotic neutrophils in patient lungs. These findings uncover a pathway of gut-lung crosstalk mediated by diet-microbiome interactions, highlighting the therapeutic potential of KD and microbiome modulation in sepsis.

Keywords:  Lactobacillus; efferocytosis; gut-lung axis; ketogenic diet; macrophages; sepsis

DOI:  https://doi.org/10.1016/j.cmet.2026.01.005
Redox Biol. 2026 Jan 12. pii: S2213-2317(26)00014-5. [Epub ahead of print]90 104016

Unveiling a novel function of Aconitase-2: attenuating lung ischemia-reperfusion injury via inhibition of pulmonary endothelial apoptosis.

Jiaojiao Sun, Bo Xu, Yijing Chen, Meng Sui, Mochi Wang, Ranming Ma, Jinbo Wu, Shiyong Teng, Qingfeng Pang, Chunxiao Hu.

  Mitochondrial dysfunction during lung ischemia-reperfusion injury (LIRI) contributes to organ dysfunction. Aconitase-2 (ACO2), by enhancing the mitochondrial tricarboxylic acid (TCA) cycle in pulmonary vascular endothelial cells (PVECs), plays a critical role in maintaining cellular energy metabolic homeostasis. Single-cell RNA sequencing was performed to characterize cellular phenotypes within the lung tissue microenvironment of I/R mice, and bulk RNA sequencing was applied to identify differentially expressed genes associated with LIRI. Our clinical cohort included 65 healthy donors and 48 patients with LIRI to evaluate the correlation between serum ACO2 levels and lung function. In vivo, using a murine I/R model, we administered an adeno-associated virus for lung-specific ACO2 overexpression, as well as an ACO2 inhibitor (tricarballylic acid), to assess their effects on lung injury. In vitro, primary PVECs were isolated and subjected to hypoxia/reoxygenation (H/R), followed by ACO2 overexpression or knockout, and treatment with the ACO2 downstream metabolite derivative 4-octyl itaconate (4-OI), to investigate its role in mitochondrial function and apoptosis. Serum ACO2 levels were reduced in LIRI patients and exhibited a significant negative correlation with impaired lung function. In I/R mice, ACO2 overexpression ameliorated mitochondrial dysfunction and attenuated lung injury, whereas ACO2 inhibition exacerbated these pathological changes. In PVECs, ACO2 overexpression enhanced mitochondrial function and reduced apoptosis; conversely, ACO2 knockout exerted opposing effects. Notably, supplementation with 4-OI mitigated mitochondrial dysfunction and cellular apoptosis induced by ACO2 deficiency. These findings suggest that ACO2 has therapeutic potential in improving mitochondrial function, reducing apoptosis, and alleviating LIRI, positioning it as a promising target for the treatment of this condition.

Keywords:  Aconitase-2; Apoptosis; Lung ischemia-reperfusion injury; Mitochondrion; Pulmonary vascular endothelial cells

DOI:  https://doi.org/10.1016/j.redox.2026.104016
Nat Commun. 2026 Feb 05.

FGF 13 functions as a regulator of the ERK/aerobic glycolysis axis in the inflammatory state during septic lung injury.

Junjie Zhu, Jiaqi Wang, Chunhui Jiang, Jie Wang, Jie Zhou, Gaozan Tong, Yuecheng Wu, Zhuoyao Ou, Junbo Ye, Enzhao Shen, Anqi Ke, Fan Li, Meifan Jiang, Jihong Ma, Litai Jin, Xiaokun Li, Weitao Cong.

Fibroblast growth factor 13 (FGF13) belongs to the FGF homologous factor subfamily, members of which lack signal peptides. In this study, we demonstrate that FGF13 is significantly downregulated in endothelial cells and macrophages in the lungs of septic patients and septic mice. However, the role of FGF13 in sepsis and the underlying mechanism are largely unknown. By using mice with conditional Fgf13 knockout and FGF13 overexpression, we find that FGF13 accelerates septic lung injury by promoting inflammatory activation of endothelial cells and macrophages. Specifically, FGF13 functions as a scaffold protein in TAK1/MEK/ERK signaling to promote hypoxia-inducible factor (HIF)-1α-regulated aerobic glycolysis in the inflammatory state. Meanwhile, the protective effect of conditional Fgf13 knockout is abolished in HIF-1α-overexpressing mice. In addition, SCH772984 (a selective antagonist of ERK signaling) abolishes the aggravation of inflammation in lungs induced by FGF13 overexpression. Our findings demonstrate that FGF13 promotes inflammatory activation upon septic lung injury through the ERK/aerobic glycolysis axis, thereby accelerating the progression of septic lung injury.

DOI: https://doi.org/10.1038/s41467-026-69014-x
Nat Commun. 2026 Feb 05.

Acute peritonitis-induced adipose CD127+ ILC1s express PD-L1 and ameliorate inflammation in mice.

Ritsu Nagata, Yuichi Akama, Pedro Goncalves, Nicolas Serafini, Tomoko Kageyama, Masami Kawasumi, Manami Satoh, Motomu Shimaoka, Hiroshi Ohno, Naoko Satoh-Takayama.

Peritonitis is an inflammation of the peritoneum primarily caused by gut perforation and consequent bacterial leakage, a known cause of sepsis. Although adipose tissue is recognized as an immunologically active organ, the involvement of adipose tissue innate lymphoid cells (ILC) in regulating peritonitis remains poorly understood. Here, we employ a cecal ligation and puncture mouse model and demonstrate that circulating CD127- group 1 ILC (ILC1) migrate into the mesenteric adipose tissue (MAT) during the inflammatory period of peritonitis. CD127- ILC1s undergo phenotypic changes to become CD127+ ILC1s, resulting in an increased number of CD127+ ILC1s in the MAT. We also show that this population of CD127+ ILC1s expresses PD-L1, exhibits low IFN-γ production, and potentially acts as a negative regulator of TNF production by γδ T cells, thereby controlling acute peritonitis. Our findings suggest that MAT-CD127+ ILC1s play an important regulatory role in acute peritonitis and may represent a potential therapeutic target for sepsis.

DOI: https://doi.org/10.1038/s41467-026-69100-0