CTRP9 induces macrophages polarization into M1 phenotype through activating JNK pathway and enhances VSMCs apoptosis in macrophages and VSMCs co-culture system

• Published in: Experimental cell research 2020-10, Vol.395 (1), p.112194, Article 112194
• Main Authors: Chen, Ji-Ying, Song, Cheng-Xiang, Lei, Sheng-Yun, Li, Jun, Zuo, An-Ju, Xu, Dan, Guo, Yuan
• Format: Article
• Language: English
• Subjects: Adiponectin - metabolism; Adiponectin - pharmacology; Animals; Apoptosis - drug effects; Co-culture system; Coculture Techniques; CTRP9; Glycoproteins - metabolism; Glycoproteins - pharmacology; JNK; Lipopolysaccharides - pharmacology; Macrophage Activation - drug effects; Macrophages - drug effects; Macrophages - metabolism; Macrophages polarization; Mice; Mitogen-Activated Protein Kinases - metabolism; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Phosphorylation - drug effects; Signal Transduction - drug effects; Up-Regulation - drug effects; VSMCs apoptosis
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2020.112194

Inflammation plays a critical role in the development of atherosclerosis (AS), which has been identified as a major predisposing factor for stroke. Macrophages and VSMCs are associated with plaque formation and progression. Macrophages can dynamically change into two main functional phenotypes, namely M1 and M2, they can produce either pro-inflammatory or anti-inflammatory factors which may affect the outcome of inflammation. As a member of CTRPs family, CTRP9 has been reported play important protective roles in the cardiovascular system. However, whether CTRP9 can regulate macrophage activation status in inflammatory responses and have effect on VSMCs behaviors in co-culture system have not been fully investigated. In the present study, using peritoneal macrophages treated with CTRP9, we found that CTRP9 facilitated macrophages towards M1 phenotype, promoted TNF-α secretion and MMPs expression. CTRP9 showed synergistic effect with LPS in inducing M1 macrophages. In macrophages-VSMCs co-culture system, apoptosis and down-regulated proliferation of VSMCs were accelerated with CTRP9-treated macrophages. Then we attempted to explore the underlying molecular mechanisms of CTRP9 resulting in M1 activation. The c-Jun NH2-terminal kinases (JNK) are members of the mitogen activated protein kinases (MAPK) family, plays a central role in the cell stress response, with outcomes ranging from cell death to cell proliferation and survival. We found JNK expression was upregulated following CTRP9 stimulation, and inhibiting JNK phosphorylation level was associated with decreased expression of M1 markers and TNF-α concentration. Moreover, VSMCs apoptosis were ameliorated after inhibition of JNK. These results suggested that CTRP9 may promote macrophage towards M1 activation status through JNK signaling pathway activation.