Targeting SLC22A5 fosters mitophagy inhibition-mediated macrophage immunity against septic acute kidney injury upon CD47-SIRPα axis blockade
Yu Jia,
Jun-Hua Li,
Bang-Chuan Hu,
Xia Huang,
Xi Yang,
Yan-Yan Liu,
Juan-Juan Cai,
Xue Yang,
Jun-Mei Lai,
Ye Shen,
Jing-Quan Liu,
Hai-Ping Zhu,
Xiang-Ming Ye,
Shi-Jing Mo
Affiliations
Yu Jia
Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, PR China
Jun-Hua Li
Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, PR China
Bang-Chuan Hu
Emergency and Intensive Care Unit Center, Intensive Care Unit, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, 310014, Zhejiang, PR China
Xia Huang
Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, PR China
Xi Yang
Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, PR China
Yan-Yan Liu
Department of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, PR China
Juan-Juan Cai
Department of Pathology, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, 310014, Zhejiang, PR China
Xue Yang
Clinical Research Institute, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, 310014, Zhejiang, PR China
Jun-Mei Lai
Center for Rehabilitation Medicine, Department of Intensive Rehabilitation Care Unit, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, Zhejiang, P.R.China
Ye Shen
Center for Rehabilitation Medicine, Department of Intensive Rehabilitation Care Unit, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, Zhejiang, P.R.China
Jing-Quan Liu
Emergency and Intensive Care Unit Center, Intensive Care Unit, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, 310014, Zhejiang, PR China
Hai-Ping Zhu
Department of Intensive Care Unit, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, Zhejiang, PR China
Xiang-Ming Ye
Center for Rehabilitation Medicine, Department of Intensive Rehabilitation Care Unit, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, Zhejiang, P.R.China; Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Department of Rehabilitation Medicine, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, 310014, Zhejiang, PR China; Corresponding author. Department of Intensive Rehabilitation Care Unit & Rehabilitation Medicine, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, 310014, PR China.
Shi-Jing Mo
Emergency and Intensive Care Unit Center, Intensive Care Unit, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, 310014, Zhejiang, PR China; Center for Rehabilitation Medicine, Department of Intensive Rehabilitation Care Unit, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou 310014, Zhejiang, P.R.China; Corresponding author. Department of Intensive Rehabilitation Care Unit & Intensive Care Unit, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College , Hangzhou, Zhejiang, 310014, PR China.
Efferocytosis of apoptotic neutrophils (PMNs) by macrophages is helpful for inflammation resolution and injury repair, but the role of efferocytosis in intrinsic nature of macrophages during septic acute kidney injury (AKI) remains unknown. Here we report that CD47 and signal regulatory protein alpha (SIRPα)—the anti-efferocytotic ‘don't eat me’ signals—are highly expressed in peripheral blood mononuclear cells (PBMCs) from patients with septic AKI and kidney samples from mice with polymicrobial sepsis and endotoxin shock. Conditional knockout (CKO) of SIRPA in macrophages ameliorates AKI and systemic inflammation response in septic mice, accompanied by an escalation in mitophagy inhibition of macrophages. Ablation of SIRPA transcriptionally downregulates solute carrier family 22 member 5 (SLC22A5) in the lipopolysaccharide (LPS)-stimulated macrophages that efferocytose apoptotic neutrophils (PMNs). Targeting SLC22A5 renders mitophagy inhibition of macrophages in response to LPS stimuli, improves survival and deters development of septic AKI. Our study supports further clinical investigation of CD47-SIRPα signalling in sepsis and proposes that SLC22A5 might be a promising immunotherapeutic target for septic AKI.
