IL-37b alleviates endothelial cell apoptosis and inflammation in Kawasaki disease through IL-1R8 pathway

Chang Jia,Zhengwang Wen,Shuchi Zhang,Xing Rong,Huixian Qiu,Maoping Chu,Chao Ni,Chao Niu,Linlin Wang,Rongzhou Wu,Yingzhi Zhuge

doi:10.1038/s41419-021-03852-z

Abstract

Kawasaki disease (KD) is an acute vasculitis of pediatric populations that may develop coronary artery aneurysms if untreated. It has been regarded as the principal cause of acquired heart disease in children of the developed countries. Interleukin (IL)-37, as one of the IL-1 family members, is a natural suppressor of inflammation that is caused by activation of innate and adaptive immunity. However, detailed roles of IL-37 in KD are largely unclear. Sera from patients with KD displayed that IL-37 level was significantly decreased compared with healthy controls (HCs). QRT-PCR and western blot analyses showed that the expression level of IL-37 variant, IL-37b, was remarkably downregulated in human umbilical vein endothelial cells (HUVECs) exposed to KD sera-treated THP1 cells. Therefore, we researched the role of IL-37b in the context of KD and hypothesized that IL-37b may have a powerful protective effect in KD patients. We first observed and substantiated the protective role of IL-37b in a mouse model of KD induced by Candida albicans cell wall extracts (CAWS). In vitro experiments demonstrated that IL-37b alleviated endothelial cell apoptosis and inflammation via IL-1R8 receptor by inhibiting ERK and NFκB activation, which were also recapitulated in the KD mouse model. Together, our findings suggest that IL-37b play an effective protective role in coronary endothelial damage in KD, providing new evidence that IL-37b is a potential candidate drug to treat KD.

Highlights

Kawasaki disease (KD) is an illness that can cause systemic immune vasculitis, which mainly has an effect on young children
To investigate the effect of IL-37 on KD, we first examined the level of IL-37 in the serum from KD patients as compared with healthy controls (HCs) and affirmed that its splice variant IL-37b might function in KD
To preliminarily confirm that IL-37 might be involved in the pathological process of KD, we first examined the level of IL-37 in the serum from KD patients compared with the HCs

Summary

Introduction

Kawasaki disease (KD) is an illness that can cause systemic immune vasculitis, which mainly has an effect on young children. The most severe complication of KD is coronary artery injury, including coronary artery dilation, coronary artery aneurysm (CAA) and stenosis. The state-of-the-art therapeutic strategy is intravenous immunoglobulin (IVIG) plus aspirin. In the absence of early intervention, about 25% of KD patients. It is urgent to explore novel and potential therapeutic strategy to clinically treat KD and its complications. Interleukin-37 (IL-37) is a newly reported member of the IL-1 family and functions as a novel anti-inflammatory cytokine to suppress inflammatory and immune response. Studies report that IL-37 plays an essential role in mediating inflammatory diseases, including arthritis[1], liver inflammation[2], and cardiovascular disease inflammation[3]

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