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.

Figure 1

Regulation of IL-38 on the IL-36 signaling pathway. IL-38, interleukin-38; IL-36, interleukin-36; IL-36R, interleukin-36 receptor; MAPKs, Mitogen-activated protein kinases; NF-kB, Nuclear factor kappa B.

Figure 2

Mechanism of IL-38 in regulating the macrophage function. (A) IL-38 regulates the phenotypic transformation of macrophages. (B) IL-38 inhibits NLRP3 activation. (C) IL-38 binds IL-1RAPL1 to regulate the macrophage function. IL-38, interleukin-38; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor; TGF-β, transforming growth factor-β; NLRP3, NOD-like receptor thermal protein domain-associated protein 3; IL1RAPL1, interleukin-1 receptor accessory protein-like 1 (–); inhibition.

Figure 3

The mechanisms of IL-38 and ischemic injury and repair after MI. (A) The mechanism of IL-38 on cardiomyocytes during ventricular remodeling. (B) The mechanism of IL-38 on tDCs during ventricular remodeling. MIRI, myocardial ischemia–reperfusion injury; IL-38, interleukin-38; IFN-γ, interferon-γ; tDCs, tolerogenic dendritic cells; Treg cells, regulatory T cells; (+), promoting effect; (-), inhibition.