Mesenchymal stromal cells inhibit NLRP3 inflammasome activation in a model of Coxsackievirus B3-induced inflammatory cardiomyopathy

Kapka Miteva,Fengquan Dong,Irene Müller,Sophie Van Linthout,Konstantinos Savvatis,Marzena Sosnowski,Kathleen Pappritz,Jochen Ringe,Carsten Tschöpe,Muhammad El-Shafeey

doi:10.1038/s41598-018-20686-6

Abstract

Inflammation in myocarditis induces cardiac injury and triggers disease progression to heart failure. NLRP3 inflammasome activation is a newly identified amplifying step in the pathogenesis of myocarditis. We previously have demonstrated that mesenchymal stromal cells (MSC) are cardioprotective in Coxsackievirus B3 (CVB3)-induced myocarditis. In this study, MSC markedly inhibited left ventricular (LV) NOD2, NLRP3, ASC, caspase-1, IL-1β, and IL-18 mRNA expression in CVB3-infected mice. ASC protein expression, essential for NLRP3 inflammasome assembly, increased upon CVB3 infection and was abrogated in MSC-treated mice. Concomitantly, CVB3 infection in vitro induced NOD2 expression, NLRP3 inflammasome activation and IL-1β secretion in HL-1 cells, which was abolished after MSC supplementation. The inhibitory effect of MSC on NLRP3 inflammasome activity in HL-1 cells was partly mediated via secretion of the anti-oxidative protein stanniocalcin-1. Furthermore, MSC application in CVB3-infected mice reduced the percentage of NOD2-, ASC-, p10- and/or IL-1β-positive splenic macrophages, natural killer cells, and dendritic cells. The suppressive effect of MSC on inflammasome activation was associated with normalized expression of prominent regulators of myocardial contractility and fibrosis to levels comparable to control mice. In conclusion, MSC treatment in myocarditis could be a promising strategy limiting the adverse consequences of cardiac and systemic NLRP3 inflammasome activation.

Highlights

In the innate immune response and is associated with cardiac injury by exacerbation of inflammation and cardiac remodeling[6]
NLRP3 inflammasome components downstream of a C-terminal caspase recruitment domain (ASC) remained unchanged as shown by unaltered left ventricle (LV) caspase 1 activity (Fig. 1I), and IL-1ß protein expression (Fig. 1J) in Coxsackievirus B3 (CVB3)-infected compared to control mice and they remained unaffected by Mesenchymal stromal cells (MSC) application
The present study extends the knowledge about the systemic immunomodulatory effects of MSC in myocarditis, showing that MSC abrogate the expression of NOD2, NLRP3 inflammasome activation and subsequent IL-1β production in macrophages (F4/80), natural killer (NK) cells (CD49b) and dendritic cells (DCs) (CD11c) of CVB3-infected mice

Summary

Introduction

In the innate immune response and is associated with cardiac injury by exacerbation of inflammation and cardiac remodeling[6]. CVB3 infection induces NLRP3 inflammasome activation in vitro and in vivo, which inhibition has been shown to significantly alleviate the severity of CVB3-induced myocarditis and to improve cardiac function[12]. We have demonstrated that intravenous (i.v.) MSC application has a cardioprotective effect in CVB3-induced inflammatory cardiomyopathy since MSC cannot be infected with CVB3, exert anti-viral effects, reduce CVB3-associated cardiomyocyte apoptosis, myocardial fibrosis, inflammation, improve left ventricle (LV) function and induce prominent systemic immunomodulation[18,19]. We could demonstrate that MSC potently inhibit the NLRP3 inflammasome activation in the heart and mediate systemic immunoregulation via abrogating NLRP3 inflammasome activation and IL-1β secretion in cells of the innate immune system, which could interrupt the inflammatory process amplification and subsequently diminish the adverse cardiac inflammation and dysfunction following myocardial injury

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