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

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, Ch...

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Autores principales:	Song CX, Chen JY, Li N, Guo Y
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	ctrp9 macrophage efferocytosis mitochondrial fission immunometabolism Pathology RB1-214 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/01acd9de6dee444abc818c1371427177
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spelling	oai:doaj.org-article:01acd9de6dee444abc818c13714271772021-12-02T13:13:15ZCTRP9 Enhances Efferocytosis in Macrophages via MAPK/Drp1-Mediated Mitochondrial Fission and AdipoR1-Induced Immunometabolism1178-7031https://doaj.org/article/01acd9de6dee444abc818c13714271772021-03-01T00:00:00Zhttps://www.dovepress.com/ctrp9-enhances-efferocytosis-in-macrophages-via-mapkdrp1-mediated-mito-peer-reviewed-article-JIRhttps://doaj.org/toc/1178-7031Cheng-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 ChinaCorrespondence: Yuan GuoDepartment of General Practice, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhuaxi Road, Jinan, 250012, People’s Republic of ChinaTel +86-531-82169092Email Guoyuanarticle2000@163.comBackground: 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, immunometabolismSong CXChen JYLi NGuo YDove Medical Pressarticlectrp9macrophageefferocytosismitochondrial fissionimmunometabolismPathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol Volume 14, Pp 1007-1017 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ctrp9 macrophage efferocytosis mitochondrial fission immunometabolism Pathology RB1-214 Therapeutics. Pharmacology RM1-950
spellingShingle	ctrp9 macrophage efferocytosis mitochondrial fission immunometabolism Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Song CX Chen JY Li N Guo Y CTRP9 Enhances Efferocytosis in Macrophages via MAPK/Drp1-Mediated Mitochondrial Fission and AdipoR1-Induced Immunometabolism
description	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 ChinaCorrespondence: Yuan GuoDepartment of General Practice, Qilu Hospital, Cheeloo College of Medicine, Shandong University, 107 Wenhuaxi Road, Jinan, 250012, People’s Republic of ChinaTel +86-531-82169092Email Guoyuanarticle2000@163.comBackground: 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
format	article
author	Song CX Chen JY Li N Guo Y
author_facet	Song CX Chen JY Li N Guo Y
author_sort	Song CX
title	CTRP9 Enhances Efferocytosis in Macrophages via MAPK/Drp1-Mediated Mitochondrial Fission and AdipoR1-Induced Immunometabolism
title_short	CTRP9 Enhances Efferocytosis in Macrophages via MAPK/Drp1-Mediated Mitochondrial Fission and AdipoR1-Induced Immunometabolism
title_full	CTRP9 Enhances Efferocytosis in Macrophages via MAPK/Drp1-Mediated Mitochondrial Fission and AdipoR1-Induced Immunometabolism
title_fullStr	CTRP9 Enhances Efferocytosis in Macrophages via MAPK/Drp1-Mediated Mitochondrial Fission and AdipoR1-Induced Immunometabolism
title_full_unstemmed	CTRP9 Enhances Efferocytosis in Macrophages via MAPK/Drp1-Mediated Mitochondrial Fission and AdipoR1-Induced Immunometabolism
title_sort	ctrp9 enhances efferocytosis in macrophages via mapk/drp1-mediated mitochondrial fission and adipor1-induced immunometabolism
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/01acd9de6dee444abc818c1371427177
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CTRP9 Enhances Efferocytosis in Macrophages via MAPK/Drp1-Mediated Mitochondrial Fission and AdipoR1-Induced Immunometabolism

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