IL‐38 attenuates myocardial ischemia–reperfusion injury by inhibiting macrophage inflammation

Abstract

Background: Reperfusion therapy is the most effective approach to resolve coronary occlusion, but myocardial injury caused by excessive inflammation during myocardial ischemia-reperfusion will also pose a new threat to health. Our prior study revealed the expression pattern of interleukin-38 (IL-38) in the peripheral blood serum of patients with ischemic cardiomyopathy and the role of IL-38 in acute myocardial infarction in mice. However, its role and potential mechanisms in myocardial ischemia/reperfusion injury (MIRI) remain to be determined. Methods and Results: The left anterior descending artery of C57BL/6 mice was transiently ligated to induce the MIRI model. We found that MIRI induced the expression of endogenous IL-38, which was mainly produced by locally infiltrating macrophages. Overexpression of IL-38 in C57BL/6 mice attenuated inflammatory injury and decreased myocardial apoptosis after myocardial ischemia-reperfusion. Furthermore, IL-38 inhibited lipopolysaccharide-induced macrophage inflammation in vitro. Cardiomyocytes cocultured with the supernatant of IL-38-and troponin I-treated macrophages showed a lower rate of apoptosis than controls.Conclusions: IL-38 attenuates MIRI by inhibiting macrophage inflammation. This inhibitory effect may be partially achieved by inhibiting the activation of NOD-like receptor pyrin domain-related protein 3 inflammasome, resulting in decreased expression of inflammatory factors and reduced cardiomyocyte apoptosis.

The emerging role of IL‐38 in diseases: A comprehensive review

“…Although reperfusion therapy was an effective method to address coronary occlusion, excessive myocardial ischemia‐reperfusion injury remains existed. IL‐38 could inhibit the activation of NLRP3 inflammasome, thereby suppressing macrophage‐mediated inflammation and reducing apoptosis in myocardium 41 . Obesity and diabetes are key risk factors for CVDs.…”

“…IL‐38 could inhibit the activation of NLRP3 inflammasome, thereby suppressing macrophage‐mediated inflammation and reducing apoptosis in myocardium. 41 Obesity and diabetes are key risk factors for CVDs. IL‐38 is able to inhibit preadipocyte differentiation by promoting GATA‐3 expression, reduce triglyceride synthesis and decrease adipocyte size to ameliorate obesity, and ameliorate insulin resistance.…”

Macrophage Heterogeneity and Its Impact on Myocardial Ischemia-Reperfusion Injury: An Integrative Review

“…This inhibitory effect is partly achieved by suppressing the activation of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome, resulting in reduced expression of inflammatory cytokines and decreased cardiomyocyte apoptosis. 109 IL-38 has demonstrated multiple beneficial effects in alleviating myocardial IR injury. It promotes the differentiation of M1 macrophages into an M2 phenotype, inhibits the activation of the NLRP3 inflammasome, and enhances the secretion of anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta.…”

Role of IL-1 Family Cytokines IL-36, IL-37, IL-38 in Osteoarthritis and Rheumatoid Arthritis: A Comprehensive Review

“… 50 The LPS-stimulated macrophages were cultured with IL-38, which showed inhibition of macrophage apoptosis, decreased expression of TNFα. 50 , 51 Similarly, IL‐38 is highly expressed in infiltrating macrophages from mice with myocardial ischemia/reperfusion injury (MIRI), and injection of IL‐38 in MIRI mice inhibits macrophage infiltration. 51 Cardiomyocytes co-cultured with IL‐38‐stimulated macrophages inhibits apoptosis of the cells.…”

“… 50 , 51 Similarly, IL‐38 is highly expressed in infiltrating macrophages from mice with myocardial ischemia/reperfusion injury (MIRI), and injection of IL‐38 in MIRI mice inhibits macrophage infiltration. 51 Cardiomyocytes co-cultured with IL‐38‐stimulated macrophages inhibits apoptosis of the cells. Interleukin-36R + macrophages accumulate in mice with abdominal aortic aneurysm (AAA), and MMP-2 and MMP-9 are highly expressed in these macrophages.…”