An unexpected role of neutrophils in clearing apoptotic hepatocytes in vivo
Luyang Cao,
Lixiang Ma,
Juan Zhao,
Xiangyu Wang,
Xinzou Fang,
Wei Li,
Yawen Qi,
Yingkui Tang,
Jieya Liu,
Shengxian Peng,
Li Yang,
Liangxue Zhou,
Li Li,
Xiaobo Hu,
Yuan Ji,
Yingyong Hou,
Yi Zhao,
Xianming Zhang,
You-yang Zhao,
Yong Zhao,
Yuquan Wei,
Asrar B Malik,
Hexige Saiyin,
Jingsong Xu
Affiliations
Luyang Cao
Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China; Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou, China
Lixiang Ma
Department of Anatomy, Histology & Embryology, Shanghai Medical College, Shanghai, China
Juan Zhao
Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
Department of Anatomy, Histology & Embryology, Shanghai Medical College, Shanghai, China
Xiaobo Hu
Clinical Laboratory, Longhua Hospital, Shanghai University of Traditional Medicine, Shanghai, China
Yuan Ji
Department of Pathology, Zhongshan Hospital Fudan University, Shanghai, China
Yingyong Hou
Department of Pathology, Zhongshan Hospital Fudan University, Shanghai, China
Yi Zhao
Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
Xianming Zhang
Program for Lung and Vascular Biology, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, and Department of Pediatrics, Division of Critical Care, Northwestern University Feinberg School of Medicine, Chicago, United States
You-yang Zhao
Program for Lung and Vascular Biology, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, and Department of Pediatrics, Division of Critical Care, Northwestern University Feinberg School of Medicine, Chicago, United States
Yong Zhao
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
Yuquan Wei
Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
Asrar B Malik
Department of Pharmacology, University of Illinois, College of Medicine, Chicago, United States
Hexige Saiyin
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
Billions of apoptotic cells are removed daily in a human adult by professional phagocytes (e.g. macrophages) and neighboring nonprofessional phagocytes (e.g. stromal cells). Despite being a type of professional phagocyte, neutrophils are thought to be excluded from apoptotic sites to avoid tissue inflammation. Here, we report a fundamental and unexpected role of neutrophils as the predominant phagocyte responsible for the clearance of apoptotic hepatic cells in the steady state. In contrast to the engulfment of dead cells by macrophages, neutrophils burrowed directly into apoptotic hepatocytes, a process we term perforocytosis, and ingested the effete cells from the inside. The depletion of neutrophils caused defective removal of apoptotic bodies, induced tissue injury in the mouse liver, and led to the generation of autoantibodies. Human autoimmune liver disease showed similar defects in the neutrophil-mediated clearance of apoptotic hepatic cells. Hence, neutrophils possess a specialized immunologically silent mechanism for the clearance of apoptotic hepatocytes through perforocytosis, and defects in this key housekeeping function of neutrophils contribute to the genesis of autoimmune liver disease.
