Exercise promotes host anti-infection activity through CNDP2 metabolite-mediated inflammasome hyperactivation
8 affiliations
- 1Beijing Life Science Academy, Beijing, China
- 2Department of Immunology, School of Basic Medical Sciences, State Key Laboratory of Molecular Oncology, Peking University, Beijing, China
- 3Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, Beijing, China
- 4Department of Immunology, School of Basic Medical Sciences, Peking University, Beijing, China
- 5Department of Sports Medicine, Peking University Third Hospital, Beijing, China
- 6Beijing Key Laboratory of Sports Injuries, Institute of Sports Medicine of Peking University, Beijing, China
- 7Department of Laboratory Medicine, Beijing Hospital, National Center for Gerontology, National Clinical Research Center for Gerontology, The Key Laboratory of Geriatrics of NHC, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
- 8CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
Abstract
Exercise can enhance the body’s ability to resist infections, but its molecular mechanisms are still unclear. Here, we found that exercise can induce a hyperactivation-like state of the NLRP3 inflammasome during infection, which enhances the body’s ability to resist infection by continuously secreting inflammatory cytokines and reducing immune cell pyroptosis. At the molecular level, exercise enhances the binding between CNDP2 and GSDMD, promoting the production of γ-Glu-Cys. γ-Glu-Cys binds to CypD and inhibits the binding between CypD and GSDMD, thereby avoiding further damage to the mitochondrial inner membrane during the occurrence of inflammasomes. Limited mitochondrial DNA leakage allows the NLRP3 inflammasome to a hyperactivate state. Our findings reveal the molecular mechanisms by which exercise enhances the body’s ability to resist infections, and provide possible standards for better guiding exercise intensity to improve anti-infection capabilities in the future. Author summary: Exercise triggers the production of numerous metabolites. Here, we discovered that exercise promotes the binding between CNDP2 and GSDMD in macrophages, leading to the generation of γ-Glu-Cys. During inflammasome activation, γ-Glu-Cys binds to mitochondrial CypD and prevents it from interacting with the GSDMD N-terminus. This restricts excessive permeabilization of the mitochondrial inner membrane, resulting in a controlled, limited release of mitochondrial DNA. Rather than suppressing the inflammasome, this controlled mitochondrial signal shifts the response into a hyperactivation-like state, characterized by sustained IL-1β secretion without rapid cell lysis. Consequently, exercise-trained macrophages exhibit prolonged and enhanced anti-infection activity. Our work identifies γ-Glu-Cys as an exercise-induced metabolite, providing a mechanistic explanation for why moderate exercise is beneficial for host defense against infections. These insights may open new avenues for developing immunomodulatory strategies that mimic the beneficial effects of exercise.
Related
- PDHA1 Hyperactivation-Mediated Glucose Metabolism Reprogramming Fuels Neutrophil NETosis and Promotes Acute Lung Injury.
- Progranulin deficiency promotes neuroinflammation through cathepsin B-mediated activation of the NLRP3 inflammasome
- Clusterin, through exercise-mediated liver-heart crosstalk, promotes heart regeneration after myocardial infarction
- Endurance exercise remodels pulmonary vein sleeve myocytes and promotes a proarrhythmic atrial substrate
- Oral Bacterial Translocation Promotes Lung Dysbiosis and Infection Risk after Spinal Cord Injury
BibTeX
@article{qian2026exercise,
title = {{Exercise promotes host anti-infection activity through CNDP2 metabolite-mediated inflammasome hyperactivation}},
author = {Yan Qian and Xiangyun Cheng and Qiannv Liu and Chunlei Wang and Chun Kong and Mengqian Li and Xiangyang Geng and Liya Ai and Mindi Zhao and Shuo Wang and Dong Jiang and Pengyan Xia},
journal = {PLOS Pathogens},
year = {2026},
month = oct,
doi = {10.1371/journal.ppat.1014554},
url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014554},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Exercise promotes host anti-infection activity through CNDP2 metabolite-mediated inflammasome hyperactivation
AU - Yan Qian
AU - Xiangyun Cheng
AU - Qiannv Liu
AU - Chunlei Wang
AU - Chun Kong
AU - Mengqian Li
AU - Xiangyang Geng
AU - Liya Ai
AU - Mindi Zhao
AU - Shuo Wang
AU - Dong Jiang
AU - Pengyan Xia
PY - 2026
DA - 2026/10/09
JO - PLOS Pathogens
DO - 10.1371/journal.ppat.1014554
UR - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014554
AB - Exercise can enhance the body’s ability to resist infections, but its molecular mechanisms are still unclear. Here, we found that exercise can induce a hyperactivation-like state of the NLRP3 inflammasome during infection, which enhances the body’s ability to resist infection by continuously secreting inflammatory cytokines and reducing immune cell pyroptosis. At the molecular level, exercise enhances the binding between CNDP2 and GSDMD, promoting the production of γ-Glu-Cys. γ-Glu-Cys binds to CypD and inhibits the binding between CypD and GSDMD, thereby avoiding further damage to the mitochondrial inner membrane during the occurrence of inflammasomes. Limited mitochondrial DNA leakage allows the NLRP3 inflammasome to a hyperactivate state. Our findings reveal the molecular mechanisms by which exercise enhances the body’s ability to resist infections, and provide possible standards for better guiding exercise intensity to improve anti-infection capabilities in the future. Author summary: Exercise triggers the production of numerous metabolites. Here, we discovered that exercise promotes the binding between CNDP2 and GSDMD in macrophages, leading to the generation of γ-Glu-Cys. During inflammasome activation, γ-Glu-Cys binds to mitochondrial CypD and prevents it from interacting with the GSDMD N-terminus. This restricts excessive permeabilization of the mitochondrial inner membrane, resulting in a controlled, limited release of mitochondrial DNA. Rather than suppressing the inflammasome, this controlled mitochondrial signal shifts the response into a hyperactivation-like state, characterized by sustained IL-1β secretion without rapid cell lysis. Consequently, exercise-trained macrophages exhibit prolonged and enhanced anti-infection activity. Our work identifies γ-Glu-Cys as an exercise-induced metabolite, providing a mechanistic explanation for why moderate exercise is beneficial for host defense against infections. These insights may open new avenues for developing immunomodulatory strategies that mimic the beneficial effects of exercise.
SN - 1553-7374
ER -