PMID- 36202053 OWN - NLM STAT- MEDLINE DCOM- 20221120 LR - 20221120 IS - 2352-3964 (Electronic) IS - 2352-3964 (Linking) VI - 85 DP - 2022 Nov TI - SIRPalpha maintains macrophage homeostasis by interacting with PTK2B kinase in Mycobacterium tuberculosis infection and through autophagy and necroptosis. PG - 104278 LID - S2352-3964(22)00460-1 [pii] LID - 10.1016/j.ebiom.2022.104278 [doi] LID - 104278 AB - BACKGROUND: To determine whether SIRPalpha can be a diagnostic marker of pulmonary tuberculosis (PTB) and the molecular mechanism of SIRPalpha 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 SIRPalpha expression in PTB patients. Cell-based assays were used to explore the regulation of macrophage function by SIRPalpha. SIRPalpha(-/-) and wide type macrophages transplanted C57BL/6J mice were used to determine the function of SIRPalpha on MTB infection in vivo. FINDINGS: SIRPalpha levels are closely correlated with the treatment outcomes among PTB patients. Cell-based assay demonstrated that MTB significantly induces the expression of SIRPalpha on macrophages. SIRPalpha deficiency enhances the killing ability of macrophages against MTB through processes that involve enhanced autophagy and reduced necroptosis of macrophages. Mechanistically, SIRPalpha forms a direct interaction with PTK2B through its intracellular C-terminal domain, thus inhibiting PTK2B activation in macrophages. Necroptosis inhibition due to SIRPalpha deficiency requires PTK2B activity. The transfer of SIRPalpha-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 SIRPalpha(-/-)-->WT treatment could decrease the inflammation and maintain the bactericidal capacity. INTERPRETATION: Our data define SIRPalpha 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. CI - Copyright (c) 2022 The Author(s). Published by Elsevier B.V. All rights reserved. FAU - Wang, Di AU - Wang D AD - 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. FAU - Lin, Yunkai AU - Lin Y AD - International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, National Center for Liver Cancer, Shanghai, China. FAU - Xu, Feihong AU - Xu F AD - Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, America. FAU - Zhang, Hui AU - Zhang H AD - Institute of Immunology and Molecular Medicine, Jining Medical University, Jining Shandong, China. FAU - Zhu, Xiaoyan AU - Zhu X AD - The Eighth Medical Center, Chinese PLA General Hospital, Beijing, China. FAU - Liu, Zhen AU - Liu Z AD - The Eighth Medical Center, Chinese PLA General Hospital, Beijing, China. FAU - Hu, Yuan AU - Hu Y AD - Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, America. FAU - Dong, Guanjun AU - Dong G AD - Institute of Immunology and Molecular Medicine, Jining Medical University, Jining Shandong, China. FAU - Sun, Bingqi AU - Sun B AD - Department of Clinical Laboratory, Shenyang Thoracic Hospital, Shenyang Liaoning, China. FAU - Yu, Yanhong AU - Yu Y AD - Department of Clinical Laboratory, Shenyang Tenth People's Hospital, Shenyang Liaoning, China. FAU - Ma, Guoren AU - Ma G AD - Ningxia No. 4 People's Hospital, Yinchuan Ningxia, China. FAU - Tang, Zhigang AU - Tang Z AD - Hunan Chest Hospital, Changsha Hunan, China. FAU - Legarda, Diana AU - Legarda D AD - Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, America. FAU - Ting, Adrian AU - Ting A AD - Department of Medicine, Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, America. FAU - Liu, Yuan AU - Liu Y AD - Program of Immunology and Cell Biology, Department of Biology, Center for Diagnostics & Therapeutics, Georgia State University, Atlanta, America. FAU - Hou, Jia AU - Hou J AD - Department of Respiratory and Critical Care Medicine, General Hospital of Ningxia Medical University, Yinchuan Ningxia, China. Electronic address: houj@live.com. FAU - Dong, Liwei AU - Dong L AD - International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, National Center for Liver Cancer, Shanghai, China. Electronic address: donliwei@126.com. FAU - Xiong, Huabao AU - Xiong H AD - Institute of Immunology and Molecular Medicine, Jining Medical University, Jining Shandong, China. Electronic address: xionghbl@yahoo.com. LA - eng PT - Journal Article PT - Meta-Analysis DEP - 20221003 PL - Netherlands TA - EBioMedicine JT - EBioMedicine JID - 101647039 RN - EC 2.7.10.2 (Focal Adhesion Kinase 2) RN - EC 2.7.10.2 (Ptk2b protein, mouse) RN - 0 (Sirpa protein, rat) RN - 0 (SIRPA protein, human) RN - EC 2.7.10.2 (PTK2 protein, human) SB - IM MH - Animals MH - Mice MH - Autophagy/genetics MH - Focal Adhesion Kinase 2/metabolism MH - Homeostasis MH - Macrophages/metabolism MH - Mice, Inbred C57BL MH - *Mycobacterium tuberculosis MH - Necroptosis MH - *Tuberculosis/microbiology MH - *Tuberculosis, Pulmonary/genetics/metabolism MH - Humans PMC - PMC9535427 OTO - NOTNLM OT - Autophagy OT - Biomarker OT - Immune response OT - Macrophage OT - Necroptosis COIS- Declaration of interests The authors declare that they have no conflict of interest. EDAT- 2022/10/07 06:00 MHDA- 2022/11/16 06:00 PMCR- 2022/10/03 CRDT- 2022/10/06 18:30 PHST- 2021/08/17 00:00 [received] PHST- 2022/08/29 00:00 [revised] PHST- 2022/09/06 00:00 [accepted] PHST- 2022/10/07 06:00 [pubmed] PHST- 2022/11/16 06:00 [medline] PHST- 2022/10/06 18:30 [entrez] PHST- 2022/10/03 00:00 [pmc-release] AID - S2352-3964(22)00460-1 [pii] AID - 104278 [pii] AID - 10.1016/j.ebiom.2022.104278 [doi] PST - ppublish SO - EBioMedicine. 2022 Nov;85:104278. doi: 10.1016/j.ebiom.2022.104278. Epub 2022 Oct 3.