4.1. Th17 cells and MI/IR
Myocardial infarction (MI), which is caused by acute and persistent ischemia and myocardial hypoxia [40]. Studies have found that Th17 cells are significantly increased on 14 days after myocardial infarction in mice. Th17 cells help the host to fight infection by recruiting neutrophils and macrophages into the infected tissue. The expression of inflammatory cytokines such as IL-6, IL-1β and TNF-α, induced or enhanced by Th17 cells, promote extracellular matrix remodelling by producing repair-related components such as MMP or proteoglycan(Figure 4). In rat models of myocardial infarction, Th17 cells were found to induce increased myocardial fibrosis through secretion of IL-17A and IL-17F. IL-17A could also promote fibrosis by promoting inflammatory cytokines, continuous infiltration of neutrophils and macrophages. trigger recruitment and activation of cardiac immune cells to the damaged site. Cell-based cardiac repair therapy enhances the cardiac function of the damaged heart muscle, but the mechanism remains controversial. In the rat model of heart failure (HF) induced by intraperitoneal injection of isoacrylate, the blockade of IL-17 production led to a decrease in myocardial fibrosis. Th17 cells may regulate myocardial fibrosis by producing MMP through the IL-17- NF-κB ligand (RANKL)/osteosinase (OPG) system in the cardiac fibroblasts[41]. Studies showed that the proportion of Th17 cells was significantly higher in the acute myocardial infarction (AMI) group compared with stable angina and healthy controls, and the proportion of Th17 cells also showed a positive correlation with IL-17 levels, indicating that Th17 cells participated in AMI development, and increased IL-17A led to increased mortality[42]. Myocardial reperfusion is the most important method to prevent cell death after myocardial ischemia. However, blood flow recovery may paradoxically lead to myocardial ischemia-reperfusion injury, accompanied by metabolic disturbances and cardiomyocyte death[43]. Both circulating Th17 cells and IL-17 levels are increased in ACS patients compared to healthy controls and stable angina patients. Most studies have concluded that high circulating levels of IL-17A circulation are associated with poor clinical outcomes. IL-17 aggravated myocardial ischemia-reperfusion injury, mainly related to IL-17 affecting Bax/Bcl-2 balance, promoting myocardial apoptosis, activation of cardiac endothelial cell E-selectors and ICAM-1 expression promoting neutrophil-endothelial cell adhesion and induction of chemokine expression, mediated local myocardial infiltration of neutrophils. Furthermore, IL-18 binding protein (IL-18BP) is a secreted 40 kDa glycoprotein. IL-18BP improves IR injury to the heart by inhibiting parts of Th17 differentiation[44]. In particular, cell recruitment (i.e. chemokine blockade) may be a powerful therapeutic strategy to reduce myocardial reperfusion injury at the onset of reperfusion[45].