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CTRP9 Enhances Efferocytosis in Macrophages via MAPK/Drp1-Mediated Mitochondrial Fission and AdipoR1-Induced Immunometabolism

Authors Song CX, Chen JY, Li N, Guo Y

Received 20 January 2021

Accepted for publication 10 March 2021

Published 23 March 2021 Volume 2021:14 Pages 1007—1017

DOI https://doi.org/10.2147/JIR.S302944

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Ning Quan


Cheng-Xiang Song,1,2 Ji-Ying Chen,2,3 Na Li,1,2 Yuan Guo3

1Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 2The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, 250012, People’s Republic of China; 3Department of General Practice, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China

Correspondence: Yuan Guo
Department of General Practice, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhuaxi Road, Jinan, 250012, People’s Republic of China
Tel +86-531-82169092
Email [email protected]

Background: Clearance of apoptotic cells (ACs) by phagocytes (efferocytosis) suppresses post-apoptotic necrosis and alleviates inflammation. Defective efferocytosis induces diseases that include atherosclerosis and autoimmune diseases. C1q/TNF-related protein 9 (CTRP9), a novel adipokine, has been reported to protect against various cardiovascular disease; however, the effect of CTRP9 on efferocytosis has not been elucidated.
Methods: 1. The efferocytosis of macrophages incubated with ACs with or without CTRP9 treatment was detected by flow cytometry (FCM) and immunostaining. The unengulfed ACs of CTRP9-KO and wild-type (WT) mice after dexamethasone injection were detected by TUNEL assay. 2. As mitochondrial fission is important for promoting efferocytosis, the effect of CTRP9 on mitochondrial fission was measured by fission/fusion-related proteins (MFN2, DRP1, MFF, and OPA1) and visualized by staining with MitoTracker. 3. On account of metabolism insults in engulfed macrophages, we conducted a two-stage efferocytosis assay, and the protective effects of CTRP9 on metabolism were investigated by Western blot.
Results: CTRP9 significantly facilitated macrophage efferocytosis, and it promoted mitochondrial fission by increasing the expression of p-DRP1 (s616) and the translocation of DRP1 from the cytoplasm to the mitochondria. The p38/Jnk-MAPK pathway was activated after treatment with 1 μg/mL CTRP9. When we blocked the activation of MAPK signaling by SB203580 and SP600125, the mediated effect on p-DRP1 (s616) was reduced. Moreover, CTRP9 increased the levels of ABCA1, PPAR-y, HIF-1a and GLUT1, as well as the release of lactate in basal and engulfed macrophages, which revealed that the metabolism of macrophages was advanced. Apoptotic cell-conditioned media (ACCM) and ACs increased the expression of adiponectin receptor 1 (AdipoR1). Down-regulation of AdipoR1 by siRNA could abrogate the immunometabolism effects of CTRP9.
Conclusion: CTRP9 promoted efferocytosis in macrophages via MAPK/drp1-mediated mitochondrial fission and AdipoR1-induced immunometabolism.

Keywords: CTRP9, macrophage, efferocytosis, mitochondrial fission, immunometabolism

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