Effects of IL-38 on Macrophages and Myocardial Ischemic Injury

Abstract

Macrophages play an important role in clearing necrotic myocardial tissues, myocardial ischemia-reperfusion injury, and ventricular remodeling after myocardial infarction. M1 macrophages not only participate in the inflammatory response in myocardial tissues after infarction, which causes heart damage, but also exert a protective effect on the heart during ischemia. In contrast, M2 macrophages exhibit anti-inflammatory and tissue repair properties by inducing the production of high levels of anti-inflammatory cytokines and fibro-progenitor cells. Interleukin (IL)-38, a new member of the IL-1 family, has been reported to modulate the IL-36 signaling pathway by playing a role similar to that of the IL-36 receptor antagonist, which also affects the production and secretion of macrophage-related inflammatory factors that play an anti-inflammatory role. IL-38 can relieve myocardial ischemia-reperfusion injury by promoting the differentiation of M1 macrophages into M2 macrophages, inhibit the activation of NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome, and increase the secretion of anti-inflammatory cytokines, such as IL-10 and transforming growth factor-β. The intact recombinant IL-38 can also bind to interleukin 1 receptor accessory protein-like 1 (IL-1RAPL1) to activate the c-jun N-terminal kinase/activator protein 1 (JNK/AP1) pathway and increase the production of IL-6. In addition, IL-38 regulates dendritic cell-induced cardiac regulatory T cells, thereby regulating macrophage polarization and improving ventricular remodeling after myocardial infarction. Accordingly, we speculated that IL-38 and macrophage regulation may be therapeutic targets for ameliorating myocardial ischemic injury and ventricular remodeling after myocardial infarction. However, the specific mechanism of the IL-38 action warrants further investigation.

Keywords: inflammation; interleukin-38; macrophages; myocardial infarction; myocardial ischemia–reperfusion injury; ventricular remodeling.