Neutrophils with low production of reactive oxygen species are activated during immune priming and promote development of arthritis
Tao Chen,
Zhen Zhou,
Yi Liu,
Jiayi Xu,
Chenxi Zhu,
Rui Sun,
Huifang Hu,
Yan Liu,
Lunzhi Dai,
Rikard Holmdahl,
Martin Herrmann,
Lulu Zhang,
Luis E. Muñoz,
Liesu Meng,
Yi Zhao
Affiliations
Tao Chen
Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China; Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
Zhen Zhou
Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China; Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
Yi Liu
Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
Jiayi Xu
Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China; Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
Chenxi Zhu
Frontiers Science Center for Disease-related Molecular Network, Sichuan University, 610041, Chengdu, Sichuan, China
Rui Sun
Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China; Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
Huifang Hu
Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China; Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
Yan Liu
Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China; Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
Lunzhi Dai
Department of Rheumatology and Immunology, National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China
Rikard Holmdahl
Medical Inflammation Research, Division of Immunology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
Martin Herrmann
Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Uniklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg and Uniklinikum Erlangen, Erlangen, Germany
Lulu Zhang
College of Foreign Languages and Cultures, Sichuan University, 610064, Chengdu, Sichuan, China
Luis E. Muñoz
Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Uniklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg and Uniklinikum Erlangen, Erlangen, Germany; Corresponding author. Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg and Uniklinikum Erlangen, Erlangen, Germany.
Liesu Meng
Department of Rheumatology, and National Joint Engineering Research Center of Biodiagnostics and Biotherapy, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, China; Corresponding author. Department of Rheumatology, and National Joint Engineering Research Center of Biodiagnostics and Biotherapy, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, 710004, China.
Yi Zhao
Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China; Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China; Corresponding author. Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 610041, Chengdu, Sichuan, China.
Rheumatoid arthritis (RA) is an inflammatory autoimmune disease mediated by immune cell dysfunction for which there is no universally effective prevention and treatment strategy. As primary effector cells, neutrophils are important in the inflammatory joint attack during the development of RA. Here, we used single-cell sequencing technology to thoroughly analyze the phenotypic characteristics of bone marrow-derived neutrophils in type II collagen (COL2)-induced arthritis (CIA) models, including mice primed and boosted with COL2. We identified a subpopulation of neutrophils with high expression of neutrophil cytoplasmic factor 1 (NCF1) in primed mice, accompanied by a characteristic reactive oxygen species (ROS) response, and a decrease in Ncf1 expression in boosted mice with the onset of arthritis. Furthermore, we found that after ROS reduction, arthritis occurred in primed mice but was attenuated in boosted mice. This bidirectional effect of ROS suggested a protective role of ROS during immune priming. Mechanistically, we combined functional assays and metabolomics identifying Ncf1-deficient neutrophils with enhanced migration, chemotactic receptor CXCR2 expression, inflammatory cytokine secretion, and Th1/Th17 differentiation. This alteration was mainly due to the metabolic reprogramming of Ncf1-deficient neutrophils from an energy supply pathway dominated by gluconeogenesis to an inflammatory immune pathway associated with the metabolism of histidine, glycine, serine, and threonine signaling, which in turn induced arthritis. In conclusion, we have systematically identified the functional and inflammatory phenotypic characteristics of neutrophils under ROS regulation, which provides a theoretical basis for understanding the pathogenesis of RA, to further improve prevention strategies and identify novel therapeutic targets.
