bims-traimu 2025-03-16 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–03–16
nine papers selected by
Yantong Wan, Southern Medical University

Trained immunity using probiotics and inactivated pathogens enhances resistance to Salmonella enterica serovar Typhimurium infection by activating the cGAS-STING signal pathway in mice and chickens.
Dietary succinate supplementation alleviates DSS-induced colitis via the IL-4Rα/Hif-1α Axis.
Corrigendum to "ScRNA-seq reveals trained immunity-engaged Th17 cell activation against Edwardsiella piscicida-induced intestinal inflammation in teleost" [Microbiol. Res. 289 (2024) 127912].
Itaconate restrains acute proinflammatory activation of microglia MG after traumatic brain injury in mice.
Immune training enhances anti-viral responses and improves outcomes in Pax5-/+ mice susceptible to chronic infection.
Divergent impact of endotoxin priming and endotoxin tolerance on macrophage responses to cancer cells.
Quantification of mitochondrial reactive oxygen species in macrophages during sepsis.
Single-cell RNA-seq data have prevalent blood contamination but can be rescued by Originator, a computational tool separating single-cell RNA-seq by genetic and contextual information.
Quantification of intracellular and mitochondrial ATP content in macrophages during lipopolysaccharide-induced inflammatory response.

J Adv Res. 2025 Mar 12. pii: S2090-1232(25)00152-3. [Epub ahead of print]

Trained immunity using probiotics and inactivated pathogens enhances resistance to Salmonella enterica serovar Typhimurium infection by activating the cGAS-STING signal pathway in mice and chickens.

Junpeng Jia, Wenxin Ji, Ningna Xiong, Jian Lin, Qian Yang.

   INTRODUCTION: Concerns about antibiotic resistance have prompted interest in alternative strategies for enhancing disease resistance, particularly in livestock and poultry production.
OBJECTIVES: This study explored the role of trained immunity in enhancing resistance to Salmonella enterica serovar Typhimurium (S. Typhimurium) infection in mice and chickens.
METHODS: We investigated the effects of probiotics and inactivated pathogenic bacterial strains on host immunity in Toll-like receptor 2-deficient mice (TLR2-/-) to assess whether these effects were related to bacterial outer membrane components such as peptidoglycan (PNG), lipoarabinomannan (LAM) and lipoteichoic acid (LTA). Bacterial genomes were evaluated for their ability to enhance the host immune system. Macrophage-depletion models were used to identify the key immune cells involved in trained immunity, with a focus on the cGAS-STING pathway.
RESULTS: Probiotics and inactivated pathogenic strains enhanced host immunity and protected against S. Typhimurium infection. As demonstrated in the TLR2-deficient mice, the effects were not dependent on bacterial outer membrane components. Instead, bacterial genomes played a significant role in activating trained immunity. Macrophages were identified as the primary cells that mediated the response with the cGAS-STING pathway playing a crucial role. The results observed using the mouse models led to investigating the potential application of trained immunity in poultry.
CONCLUSION: Trained immunity activated by probiotics and inactivated bacterial pathogens enhanced resistance against S. Typhimurium infection via macrophage activation and involved the cGAS-STING pathway. These findings highlight the potential of trained immunity as an alternative strategy for disease prevention in both livestock and poultry.

Keywords:  Bacterial genome; Macrophages; S. Typhimurium; Trained immunity; cGAS-STING pathway

DOI:  https://doi.org/10.1016/j.jare.2025.03.011
Int Immunopharmacol. 2025 Mar 13. pii: S1567-5769(25)00398-4. [Epub ahead of print]152 114408

Dietary succinate supplementation alleviates DSS-induced colitis via the IL-4Rα/Hif-1α Axis.

Laiying Liang, Buyun Dang, Xiaomei Ouyang, Xianling Zhao, Yongdong Huang, Ying Lin, Xiaoshen Cheng, Guijing Xie, Junhui Lin, Peng Mi, Zhenyu Ye, Bayasi Guleng, Shih-Chin Cheng.

  Inflammatory bowel disease (IBD) remains a pressing global health challenge, necessitating novel therapeutic strategies. Succinate, a metabolite known for its role in type 2 immunity and tuft cell activation in the small intestine, presents its potential in IBD management. However, its impact on colonic inflammation has not been explored. Here, we demonstrate that succinate administration induces a type 2 immune response, significantly alleviating dextran sulfate sodium (DSS)-induced colonic inflammation. Succinate enhances antibacterial capacity, reduces intestinal permeability, and reshapes the colonic cytokine milieu. Mechanistically, succinate promotes myeloid cell expansion in peripheral blood, mesenteric lymph nodes, and the colonic lamina propria. The protective effects of succinate were abolished in Ccr2-/- mice, confirming the role of monocyte recruitment, but persisted in Rag1-/- mice, indicating independence from adaptive immunity. Adoptive transfer of monocytes from succinate-treated donors mitigated intestinal inflammation in recipient mice. Transcriptomic analysis revealed heightened expression of Il1b and Il6, and higher lactate production in monocytes upon lipopolysaccharide (LPS) stimulation, highlighting a reprogrammed pro-inflammatory trained immunity phenotype. Finally, we identify the IL-4Rα/Hif-1α axis is critical for succinate-mediated protection. These findings reveal the ability of succinate to reprogram monocytes into protective intestinal macrophages via induction of type 2 response, restoring homeostasis through enhanced barrier function and immune modulation. Our study positions thus uncover succinate as a promising therapeutic candidate for IBD.

Keywords:  Colitis; Hif-1α; IL-4; Succinate; Type 2 immunity

DOI:  https://doi.org/10.1016/j.intimp.2025.114408
Microbiol Res. 2025 Mar 08. pii: S0944-5013(25)00093-X. [Epub ahead of print] 128137

Corrigendum to "ScRNA-seq reveals trained immunity-engaged Th17 cell activation against Edwardsiella piscicida-induced intestinal inflammation in teleost" [Microbiol. Res. 289 (2024) 127912].

Jin Yang, Shu Cui, Boning Shao, Yanbo Zhao, Zhuang Wang, Qin Liu, Yuanxing Zhang, Dahai Yang.

DOI: https://doi.org/10.1016/j.micres.2025.128137
Sci Transl Med. 2025 Mar 12. 17(789): eadn2635

Itaconate restrains acute proinflammatory activation of microglia MG after traumatic brain injury in mice.

Ning Liu, Yinghua Jiang, Yuwen Xiu, Giovane G Tortelote, Winna Xia, Yingjie Wang, Yadan Li, Samuel Shi, Jinrui Han, Charles Vidoudez, Aim Niamnud, Mitchell D Kilgore, Di Zhou, Mengxuan Shi, Stephen A Graziose, Jia Fan, Prasad V G Katakam, Aaron S Dumont, Xiaoying Wang.

Traumatic brain injury (TBI) rapidly triggers proinflammatory activation of microglia, contributing to secondary brain damage post-TBI. Although the governing role of energy metabolism in shaping the inflammatory phenotype and function of immune cells has been increasingly recognized, the specific alterations in microglial bioenergetics post-TBI remain poorly understood. Itaconate, a metabolite produced by the enzyme aconitate decarboxylase 1 [IRG1; encoded by immune responsive gene 1 (Irg1)], is a pivotal metabolic regulator in immune cells, particularly in macrophages. Because microglia are macrophages of the brain parenchyma, the IRG1/itaconate pathway likely modulates microglial inflammatory responses. In this study, we explored the role of the IRG1/itaconate pathway in regulating microglial bioenergetics and inflammatory activation post-TBI using a mouse controlled cortical impact (CCI) model. We isolated microglia before and 4 and 12 hours after TBI and observed a swift but transient increase in glycolysis coupled with a prolonged disruption of mitochondrial metabolism after injury. Despite an up-regulation of Irg1 expression, itaconate in microglia declined after TBI. Microglia-specific Irg1 gene knockout (Irg1-Mi-KO) exacerbated metabolic changes, intensified proinflammatory activation and neurodegeneration, and worsened certain long-term neurological deficits. Supplementation with 4-octyl itaconate (OI) reinstated the use and oxidative metabolism of glucose, glutamine, and fatty acid, thereby enhancing microglial bioenergetics post-TBI. OI supplementation also attenuated proinflammatory activation and neurodegeneration and improved long-term neurological outcomes. These results suggest that therapeutically targeting the itaconate pathway could improve microglial energy metabolism and neurological outcomes after TBI.

DOI: https://doi.org/10.1126/scitranslmed.adn2635
EMBO Mol Med. 2025 Mar 13.

Immune training enhances anti-viral responses and improves outcomes in Pax5-/+ mice susceptible to chronic infection.

Zhe Lu, Olivia Stencel, Wei Liu, Eleni Vasileiou, Haifeng C Xu, Piyush Pandey, Paweł Stachura, Abdelrahman Elwy, Anastassia Tsombal, Ann-Sophie Mai, Franziska Auer, Mina N F Morcos, Maximilian Seidl, Sarah Koziel, Peter-Martin Bruch, Sascha Dietrich, Sarah Elitzur, Gunther Hartmann, Karl S Lang, Stefan Janssen, Ute Fischer, Sanil Bhatia, Philipp A Lang, Arndt Borkhardt, Julia Hauer, Aleksandra A Pandyra.

  Viral infections pose a significant global burden. Host susceptibility to pathogens is determined by many factors including genetic variation that can lead to immunodeficient or dysregulated antiviral immune responses. Pax5 heterozygosity (Pax5-/+), resulting in reduced PAX5 levels in mice, mimics germline or somatic PAX5 dysregulation contributing to diseases such as childhood B-cell precursor acute lymphoblastic leukemia (B-ALL). In contrast to the well-characterized roles of PAX5 during early B-cell development, little is known about how Pax5 heterozygosity impacts antiviral responses. We infected Pax5-/+ mice with the noncytopathic Lymphocytic Choriomeningitis Virus (LCMV) and found that infection with the chronic Docile strain resulted in decreased survival of Pax5-/+ mice. While early adaptive CD8+ T-cell (CTL) immunity was robust in Pax5-/+ mice, LCMV-specific neutralizing antibody production was compromised leading to impaired long-term viral clearance and a pro-inflammatory milieu in the bone marrow (BM). Here we show that survival outcomes were improved upon prophylactic treatment with the β-glucan immune trainer through induction of heterologous protection against chronic infection. β-Glucan enhanced viral clearance, CTL immunity, neutralizing antibody production and reduced monocyte immunosuppression in multiple LCMV-resident host organs. New insight from this study will help design effective prophylactic treatment strategies against chronic viral infections, particularly in genetically predisposed susceptible hosts.

Keywords:  Chronic Infection; LCMV; PAX5; Trained Immunity; β-glucan

DOI:  https://doi.org/10.1038/s44321-025-00208-4
Cell Immunol. 2025 Mar 01. pii: S0008-8749(25)00019-X. [Epub ahead of print]411-412 104934

Divergent impact of endotoxin priming and endotoxin tolerance on macrophage responses to cancer cells.

Konkonika Roy, Tomasz Jędrzejewski, Justyna Sobocińska, Paulina Spisz, Bartosz Maciejewski, Nadine Hövelmeyer, Benedetta Passeri, Sylwia Wrotek.

  Endotoxin tolerance (ET) is an adaptive phenomenon that arises from the repeated exposure of immune cells, such as macrophages, to endotoxins like lipopolysaccharide (LPS). Initially, when macrophages are activated by LPS, they produce inflammatory mediators that drive the primary immune response. However, this response is significantly diminished during the establishment of ET, creating an immunosuppressive environment. This environment can facilitate the development and progression of malignant conditions, including cancer. Our research focused on the interactions between immune cells and the tumor microenvironment under ET conditions. Through comprehensive in vivo and in vitro studies employing various research techniques, we have demonstrated that interactions between endotoxin-tolerant macrophages (MoET) and cancer cells contribute to a pro-tumorigenic condition. Notably, we observed that MoET adapt a pro-tumorigenic, immunosuppressive M2 phenotype (CD163 expression). These macrophages involves distinct metabolic pathways, not depending solely on glycolysis and oxidative phosphorylation. Furthermore, our in vivo findings revealed macrophage infiltration within tumors under both ET and non-ET conditions, highlighting the suppressed immune landscape in the presence of ET. These findings suggest that ET plays a pivotal role in shaping tumor-associated immune responses and that targeting ET pathways could offer a novel and promising therapeutic approach for cancer treatment.

Keywords:  Endotoxin tolerance; Immunosuppression; M1/M2 phenotype; Tumor microenvironment; cancer

DOI:  https://doi.org/10.1016/j.cellimm.2025.104934
Methods Cell Biol. 2025 ;pii: S0091-679X(24)00018-9. [Epub ahead of print]194 59-75

Quantification of mitochondrial reactive oxygen species in macrophages during sepsis.

Kanmani Suganya, Paulraj Kanmani, Guochang Hu.

  Sepsis is the leading causes of death globally, arising from an imbalanced host response to severe infection. It leads to multi-organ failure and poor outcomes in septic patients due to compromised glucose and lipid oxidation, reduced oxygen consumption, elevated levels of circulating substrates, and impaired mitochondrial function. Mitochondria, essential cellular organelles, play a vital role in regulating various cellular activities and the host immune response to infection. Pathogens, particularly bacteria, often disrupt mitochondrial functions to dysregulate host immunity. Additionally, the mitochondrial function is closely associated with most host immune responses, making mitochondria crucial in maintaining host homeostasis during infection. The intrinsic inflammatory response triggered by pathogens in sepsis impairs mitochondrial function, resulting in excessive production of mitochondrial reactive oxygen species (ROS) and subsequently damage to multiple organs. Here, we present a simple protocol for assessing mitochondrial ROS levels in bone marrow-derived macrophages (BMDMs) isolated from mice. We observed a higher level of ROS generation in lipopolysaccharide (LPS)-treated BMDMs, indicating the effectiveness and efficiency of our designed protocol for assessing mitochondrial ROS generation in vitro.

Keywords:  Inflammation; Lipopolysaccharide; Macrophage; Mitochondria; Reactive oxygen species; Sepsis

DOI:  https://doi.org/10.1016/bs.mcb.2024.01.005
Genome Biol. 2025 Mar 11. 26(1): 52

Single-cell RNA-seq data have prevalent blood contamination but can be rescued by Originator, a computational tool separating single-cell RNA-seq by genetic and contextual information.

Thatchayut Unjitwattana, Qianhui Huang, Yiwen Yang, Leyang Tao, Youqi Yang, Mengtian Zhou, Yuheng Du, Lana X Garmire.

  Single-cell RNA sequencing (scRNA-seq) data from complex human tissues have prevalent blood cell contamination during the sample preparation process. They may also comprise cells of different genetic makeups. We propose a new computational framework, Originator, which deciphers single cells by genetic origin and separates immune cells of blood contamination from those of expected tissue-resident cells. We demonstrate the accuracy of Originator at separating immune cells from the blood and tissue as well as cells of different genetic origins, using a variety of artificially mixed and real datasets, including pancreatic cancer and placentas as examples.

Keywords:  Blood cell; Cancer; Contamination; Genetic origin; Placenta; ScRNA-seq; Tissue heterogeneity

DOI:  https://doi.org/10.1186/s13059-025-03495-9
Methods Cell Biol. 2025 ;pii: S0091-679X(24)00019-0. [Epub ahead of print]194 77-92

Quantification of intracellular and mitochondrial ATP content in macrophages during lipopolysaccharide-induced inflammatory response.

Paulraj Kanmani, Guochang Hu.

  Sepsis, a condition characterized by systemic infection that becomes aggravated and dysregulated, is a significant cause of mortality in critically ill patients. Emerging evidence suggests that severe sepsis is often accompanied by alterations in cell metabolism, particularly mitochondrial dysfunction, resulting in multiorgan failure. Normally, metabolically active cells or tissues exhibit higher levels of mitochondrial turnover, respiration, and adenosine triphosphate (ATP) synthesis. However, during sepsis, these processes become overwhelmed or dysregulated, leading to impaired ATP production in mitochondria. Here, we present two straightforward protocols for quantifying ATP production from mitochondria in bone marrow-derived macrophages (BMDMs). Our workflow facilitates the easy isolation of BMDMs and mitochondria from BMDMs treated with lipopolysaccharide (LPS), the major cell wall component of Gram-negative bacteria. We quantified intracellular and mitochondrial ATP production in macrophages in vitro using this protocol. The results indicated a decrease in mitochondrial ATP content in BMDMs in response to LPS. With minimal adjustments, this method can be adapted for use with various human and mouse primary cells and cell lines.

Keywords:  ATP; Inflammation; Lipopolysaccharide; Macrophage; Mitochondria; Sepsis

DOI:  https://doi.org/10.1016/bs.mcb.2024.01.006