摘要
Myocardial ischemia–reperfusion injury(MIRI)is a major hindrance to the success of cardiac reperfusion therapy.Although increased neutrophil infiltration is a hallmark of MIRI,the subtypes and alterations of neutrophils in this process remain unclear.Here,we performed single-cell sequencing of cardiac CD45^(+)cells isolated from the murine myocardium subjected to MIRI at six-time points.We identified diverse types of infiltrating immune cells and their dynamic changes during MIRI.Cardiac neutrophils showed the most immediate response and largest changes and featured with functionally heterogeneous subpopulations,including Ccl3^(hi)Neu and Ym-1^(hi)Neu,which were increased at 6 h and 1 d after reperfusion,respectively.Ym-1^(hi)Neu selectively expressed genes with protective effects and was,therefore,identified as a novel specific type of cardiac cell in the injured heart.Further analysis indicated that neutrophils and their subtypes orchestrated subsequent immune responses in the cardiac tissues,especially instructing the response of macrophages.The abundance of Ym-1^(hi)Neu was closely correlated with the therapeutic efficacy of MIRI when neutrophils were specifically targeted by anti-Lymphocyte antigen 6 complex locus G6D(Ly6G)or anti-Intercellular cell adhesion molecule-1(ICAM-1)neutralizing antibodies.In addition,a neutrophil subtype with the same phenotype as Ym-1^(hi)Neu was detected in clinical samples and correlated with prognosis.Ym-1 inhibition exacerbated myocardial injury,whereas Ym-1 supplementation significantly ameliorated injury in MIRI mice,which was attributed to the tilt of Ym-1 on the polarization of macrophages toward the repair phenotype in myocardial tissue.Overall,our findings reveal the antiinflammatory phenotype of Ym-1^(hi)Neu and highlight its critical role in myocardial protection during the early stages of MIRI.
作者
董亚兰
康真玉
张子力
张永强
周海锋
刘艳飞
帅欣欣
李君仪
殷梁青青
王埙埙
马彦
范恒
Feng Jiang
林志豪
丁从珠
金渊真
Alexey Sarapultsev
李芳菲
张戈
谢天
尹长军
程翔
罗珊珊
刘玥
胡德胜
Yalan Dong;Zhenyu Kang;Zili Zhang;Yongqiang Zhang;Haifeng Zhou;Yanfei Liu;Xinxin Shuai;Junyi Li;Liangqingqing Yin;Xunxun Wang;Yan Ma;Heng Fan;Feng Jiang;Zhihao Lin;Congzhu Ding;Kim Yun Jin;Alexey Sarapultsev;Fangfei Li;Ge Zhang;Tian Xie;Changjun Yin;Xiang Cheng;Shanshan Luo;Yue Liu;Desheng Hu(Department of Integrated Traditional Chinese and Western Medicine,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China;Hubei Key Laboratory of Biological Targeted Therapy,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China;Nanjing Drum Tower Hospital,Clinical College of Traditional Chinese and Western Medicine,Nanjing University of Chinese Medicine,Nanjing 210008,China;National Clinical Research Center for Chinese Medicine Cardiology,Xiyuan Hospital,Chinese Academy of Chinese Medical Sciences,Beijing 100091,China;Department of Cardiology,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China;Department of International Education,Tianjin University of Traditional Chinese Medicine,Tianjin 300193,China;Institute of Neuroscience,School of Medicine,Xiamen University,Xiamen 361102,China;School of Traditional Chinese Medicine,Xiamen University Malaysia,Sepang 43900,Malaysia;School of Medical Biology,South Ural State University,Chelyabinsk 620049,Russia;Shum Yiu Foon Sum Bik Chuen Memorial Centre for Cancer and Inflammation Research(CCIR),School of Chinese Medicine,Hong Kong Baptist University,Hong Kong 999077,China;Institute of Integrated Bioinfomedicine and Translational Science,School of Chinese Medicine,Hong Kong Baptist University,Hong Kong 999077,China;Division of Vascular Surgery,The First Affiliated Hospital of Sun Yat-sen University,Guangzhou 510080,China;Institute of Precision Medicine,The First Affiliated Hospital of Sun Yat-sen University,Guangzhou 510080,China;Institute for Cardiovascular Prevention(IPEK),Ludwig-Maximilians-University,Munich 80336,Germany;Institute of Hematology,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China;China-Russia Medical Research Center for Stress Immunology,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China)
基金
supported by the National Natural Science Foundation of China(82022076,81974249,82070136,82104488,and 82305194)
the Postdoctoral Science Foundation of China(2023M731222,and 2020T130040ZX)
the Foundation of Hubei Key Laboratory of Biological Targeted Therapy(2023swbx021)。
