SIRPα maintains macrophage homeostasis by interacting with PTK2B kinase in Mycobacterium tuberculosis infection and through autophagy and necroptosis
Di Wang,
Yunkai Lin,
Feihong Xu,
Hui Zhang,
Xiaoyan Zhu,
Zhen Liu,
Yuan Hu,
Guanjun Dong,
Bingqi Sun,
Yanhong Yu,
Guoren Ma,
Zhigang Tang,
Diana Legarda,
Adrian Ting,
Yuan Liu,
Jia Hou,
Liwei Dong,
Huabao Xiong
Affiliations
Di Wang
International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, National Center for Liver Cancer, Shanghai, China; Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, America; The Eighth Medical Center, Chinese PLA General Hospital, Beijing, China
Yunkai Lin
International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, National Center for Liver Cancer, Shanghai, China
Feihong Xu
Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, America
Hui Zhang
Institute of Immunology and Molecular Medicine, Jining Medical University, Jining Shandong, China
Xiaoyan Zhu
The Eighth Medical Center, Chinese PLA General Hospital, Beijing, China
Zhen Liu
The Eighth Medical Center, Chinese PLA General Hospital, Beijing, China
Yuan Hu
Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, America
Guanjun Dong
Institute of Immunology and Molecular Medicine, Jining Medical University, Jining Shandong, China
Bingqi Sun
Department of Clinical Laboratory, Shenyang Thoracic Hospital, Shenyang Liaoning, China
Yanhong Yu
Department of Clinical Laboratory, Shenyang Tenth People's Hospital, Shenyang Liaoning, China
Guoren Ma
Ningxia No. 4 People's Hospital, Yinchuan Ningxia, China
Zhigang Tang
Hunan Chest Hospital, Changsha Hunan, China
Diana Legarda
Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, America
Adrian Ting
Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, America
Yuan Liu
Program of Immunology and Cell Biology, Department of Biology, Center for Diagnostics & Therapeutics, Georgia State University, Atlanta, America
Jia Hou
Department of Respiratory and Critical Care Medicine, General Hospital of Ningxia Medical University, Yinchuan Ningxia, China; Corresponding author at: Department of Respiratory and Critical Care Medicine, General Hospital of Ningxia Medical University, Yinchuan Ningxia, China.
Liwei Dong
International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, National Center for Liver Cancer, Shanghai, China; Corresponding author at: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, China.
Huabao Xiong
Institute of Immunology and Molecular Medicine, Jining Medical University, Jining Shandong, China; Corresponding author at: Institute of Immunology and Molecular Medicine, Jining Medical University, Jining Shandong, China.
Summary: Background: To determine whether SIRPα can be a diagnostic marker of pulmonary tuberculosis (PTB) and the molecular mechanism of SIRPα regulating macrophages to kill Mycobacterium tuberculosis (MTB). Methods: Meta-analysis combined with subsequent qRT-PCR, western-blotting and flow cytometry assay were used to detect SIRPα expression in PTB patients. Cell-based assays were used to explore the regulation of macrophage function by SIRPα. SIRPα−/- and wide type macrophages transplanted C57BL/6J mice were used to determine the function of SIRPα on MTB infection in vivo. Findings: SIRPα levels are closely correlated with the treatment outcomes among PTB patients. Cell-based assay demonstrated that MTB significantly induces the expression of SIRPα on macrophages. SIRPα deficiency enhances the killing ability of macrophages against MTB through processes that involve enhanced autophagy and reduced necroptosis of macrophages. Mechanistically, SIRPα forms a direct interaction with PTK2B through its intracellular C-terminal domain, thus inhibiting PTK2B activation in macrophages. Necroptosis inhibition due to SIRPα deficiency requires PTK2B activity. The transfer of SIRPα-deficient bone marrow-derived macrophages (BMDMs) into wild type mice resulted in a drop of bacterial load in the lungs but an enhancement of inflammatory lung damage, and the combination of ulinastatin and SIRPα−/−→WT treatment could decrease the inflammation and maintain the bactericidal capacity. Interpretation: Our data define SIRPα a novel biomarker for tuberculosis infection and underlying mechanisms for maintaining macrophage homeostasis. Funding: This work was financially supported by the Chinese National Natural Science Foundation project (No.81401635). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
