Journal of Inflammation Research (Dec 2021)
Monomeric CRP Aggravates Myocardial Injury After Myocardial Infarction by Polarizing the Macrophage to Pro-Inflammatory Phenotype Through JNK Signaling Pathway
Abstract
Zhimin Zha,1,* Yujia Cheng,2,3,* Lu Cao,2 Yanxia Qian,2 Xinjian Liu,3,4 Yan Guo,1 Junhong Wang2 1Department of Gerontology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Cardiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, People’s Republic of China; 3Key Laboratory of Antibody Techniques of National Health Commission, Nanjing Medical University, Nanjing, People’s Republic of China; 4Department of Pathogen Biology, Nanjing Medical University, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yan Guo; Junhong WangDepartment of Gerontology, The First Affiliated Hospital with Nanjing Medical University, No. 300 Guangzhou Road, Gulou District, Nanjing City, Jiangsu Province, 210009, People’s Republic of ChinaTel +86-25-68305083; +86-25-68308273Email [email protected]; [email protected]: A polarized macrophage response plays a critical role in the pathophysiological process of myocardial infarction (MI). Several studies have shown a pro-inflammatory role for monomeric C-reactive protein (mCRP) in cardiovascular disease. However, the mechanism of how mCRP regulates macrophage phenotype switching remains unknown. In the present study, the effect of mCRP on macrophage polarization and its pathological function in myocardial repair after myocardial infarction was investigated.Methods: MI was induced by permanent ligation of the left anterior descending coronary artery in ICR mice. Adult mice were injected with mCRP (2.5 mg/kg) with or without SP600125 (15 mg/kg, JNK inhibitor) 45 min before MI. The cardiac function, scar size as well as cardiac fibrosis, infiltration of inflammatory cells, and the level of proteins in the JNK signaling pathway in infarcted myocardium were assessed. In addition, the phenotypic characterization of macrophages was further measured by ELISA, flow cytometry and quantitative RT-PCR in cultured THP-1 cells or peritoneal macrophages.Results: Cardiac function deterioration, ventricular dilatation and fibrosis were exacerbated in mice pretreatment with mCRP following MI. Meanwhile, an increased accumulation of infiltrated inflammatory cells in infarcted myocardium was observed in the mCRP group. Moreover, activation of the JNK signaling pathway was markedly elevated in mCRP treated animals post-MI. In contrast, pharmacological inhibition of JNK phosphorylation activity by SP600125 muted the detrimental effects of mCRP in MI mice. Furthermore, in vitro and in vivo co-culture experiments showed that mCRP shifted macrophage polarization towards pro-inflammatory phenotypes, and this polarization could be abolished by sp600125.Conclusion: Taken together, our results imply that mCRP impairs myocardial repair after myocardial infarction by polarizing the macrophages into the pro-inflammatory M1 phenotype via the JNK-dependent pathway.Keywords: myocardial infarction, monomeric CRP, inflammation, macrophage polarization, JNK pathway
