Targeting IRE1 endoribonuclease activity alleviates cardiovascular lesions in a murine model of Kawasaki disease vasculitis.

Stefanie Marek-Iannucci,Syed M Hamid,Begüm Kocatürk,Asli B Ozdemir,Takao Iwawaki,Asli D Yildirim,Angela C Gomez,Rebecca A Porritt,Magali Noval Rivas,Ebru Erbay,Michael C Fishbein,Moshe Arditi

doi:10.1172/jci.insight.157203

Abstract

Kawasaki disease (KD) is the leading cause of noncongenital heart disease in children. Studies in mice and humans propound the NLRP3/IL-1β pathway as the principal driver of KD pathophysiology. Endoplasmic reticulum (ER) stress can activate the NLRP3 inflammasome, but the potential implication of ER stress in KD pathophysiology has not been investigated to our knowledge. We used human patient data and the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis to characterize the impact of ER stress on the development of cardiovascular lesions. KD patient transcriptomics and single-cell RNA sequencing of the abdominal aorta from LCWE-injected mice revealed changes in the expression of ER stress genes. Alleviating ER stress genetically, by conditional deletion of inositol-requiring enzyme 1 (IRE1) in myeloid cells, or pharmacologically, by inhibition of IRE1 endoribonuclease (RNase) activity, led to significant reduction of LCWE-induced cardiovascular lesion formation as well as reduced caspase-1 activity and IL-1β secretion. These results demonstrate the causal relationship of ER stress to KD pathogenesis and highlight IRE1 RNase activity as a potential new therapeutic target.

Highlights

Kawasaki disease (KD), a febrile systemic vasculitis of unknown etiology, predominantly affects children under 5 years of age [1,2,3]
While there is strong evidence supporting the crucial role of NLRP3 inflammasome activation and IL-1β secretion in cardiovascular lesion development during human KD and in murine models of KD vasculitis [7, 10, 41, 42], and endoplasmic reticulum (ER) stress is an established inducer of NLRP3 inflammasome activity [33, 43], the role of ER-stress during KD vasculitis has not previously been investigated
Based on publicly available human patient transcriptomics datasets, bulk RNA sequencing and single-cell RNA sequencing from murine KD vasculitis, we show that KD development is associated with increased expression of ER stress signature genes, including inositol-requiring enzyme 1 (IRE1)/X-box-binding protein1 (XBP1) target genes

Summary

Introduction

Kawasaki disease (KD), a febrile systemic vasculitis of unknown etiology, predominantly affects children under 5 years of age [1,2,3]. The Leucine-rich repeat (LRR)-containing protein 3 (NLRP3) inflammasome and interleukin-1β (IL-1β) pathway have been shown to be major drivers of cardiovascular lesion formation in this model [8,9,10,11]. Under conditions of ER stress, IRE1 autophosphorylates, activating its ability to splice the mRNA encoding X-box-binding protein (XBP1), an important transcription factor in the UPR pathway [29]. In addition to activating the UPR, disruption of calcium homeostasis is known to activate the NLRP3 inflammasome [34]. Given these established connections between ER stress and NLRP3 inflammasome activation, we asked whether ER stress-mediated IRE1 activation plays a role in the development of cardiovascular lesions in KD. We demonstrate that genetic and pharmacological modulations of the IRE1 pathway mitigate inflammation by hindering NLRP3 activation and IL-1β secretion

Methods

Results

Conclusion