Interleukin‐38 alleviates cardiac remodelling after myocardial infarction

Abstract

Excessive immune‐mediated inflammatory reaction plays a deleterious role in ventricular remodelling after myocardial infarction (MI). Interleukin (IL)‐38 is a newly characterized cytokine of the IL‐1 family and has been reported to exert a protective effect in some autoimmune diseases. However, its role in cardiac remodelling post‐MI remains unknown. In this study, we found that the expression of IL‐38 was increased in infarcted heart after MI induced in C57BL/6 mice by permanent ligation of the left anterior descending artery. In addition, our data showed that ventricular remodelling after MI was significantly ameliorated after recombinant IL‐38 injection in mice. This amelioration was demonstrated by better cardiac function, restricted inflammatory response, attenuated myocardial injury and decreased myocardial fibrosis. Our results in vitro revealed that IL‐38 affects the phenotype of dendritic cells (DCs) and IL‐38 plus troponin I (TNI)‐treated tolerogenic DCs dampened adaptive immune response when co‐cultured with CD4+T cells. In conclusion, IL‐38 plays a protective effect in ventricular remodelling post‐MI, one possibility by influencing DCs to attenuate inflammatory response. Therefore, targeting IL‐38 may hold a new therapeutic potential in treating MI.

Interleukin-36 Cytokine/Receptor Signaling: A New Target for Tissue Fibrosis

“…Subsequent studies in various models of fibrosis later revealed additional evidence of a possible molecular link between IL-36R and fibrogenesis. In recent years, IL-36R has gained much attention in the field of fibrosis, owing to the discovery of IL-36R-functional associated molecules such as its agonists (IL-36α, β, and γ) and antagonists (IL-36Ra and IL-38), which are involved in the fibrosis of multiple tissues such as lung, kidneys, and heart [ 15 , 16 , 21 , 22 , 88 , 89 , 90 ]. Taken together, this body of work points out a new avenue of research centered on understanding the mechanisms involved in the IL-36R mediated fibrosis progression, which we will review here.…”

“…The functional and morphological consequences of myocardial infarction have been highly targeted areas in the field of heart disease. Fibrosis developed after myocardial infarction (MI) impairs the contractile capability, leading to heart failure (HF) [ 89 ]. Studies have shown that immune responses drive many of the processes that influence cardiac function in MI [ 103 ].…”

“…The presence of IL-38 (an IL-36R inhibitor) in MI patients has also drawn attention to the role of the IL- 1 family as functional determinants of cardiac function [ 109 ]. Wei et al followed up their 2015 investigation of IL-38′s contribution to MI pathology with subsequent in vivo mouse studies, which showed that treatment with recombinant IL-38 resulted in a disruption of cardiac fibrosis and improved ventricular function [ 89 ]. This observation reinforced the significance of IL-36R and its antagonists in the development of cardiac fibrosis.…”

“…Wei and colleagues found that IL-38, an IL-36R inhibitor, reduced immune cell (neutrophil and macrophage) presence after MI [ 89 ]. In vitro studies revealed that IL-38 prevents DCs from maturing into CD40 + CD86 + MHC-II (major histocompatibility complex class II) + cells and impedes their ability to produce pro-inflammatory cytokines IL-23, TNFα (tumor necrosis factor alpha) and IFNγ (interferon gamma) [ 89 ]. It is well established that these cytokines are linked to leukocyte recruitment and activation [ 121 , 122 , 123 , 124 ].…”

“…It is well established that these cytokines are linked to leukocyte recruitment and activation [ 121 , 122 , 123 , 124 ]. It was also reported that IL-38 treatment downregulated CD4 T cells accumulation, but upregulated the regulatory T cell subgroup called Foxp3+ Treg, which can repress inflammation and inhibit remodeling [ 89 , 125 ]. In summary, the current data implies that IL-36 mediates cardiac fibrogenesis in a comprehensive mechanism by inducing the maturation of DCs, increasing the activation of CD4 + T cells, and reducing the population of T regulatory cells.…”