期刊
BASIC RESEARCH IN CARDIOLOGY
卷 115, 期 4, 页码 -出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00395-020-0803-5
关键词
Cardiomyopathy; Inflammation; Immune cells; Desmosome; Desmoglein; Chronic disease progression
资金
- Projekt DEAL
- Interdisciplinary Center for Clinical Research within the Faculty of Medicine at Rheinisch-Westfalische Technische Hochschule Aachen University [T9-2, K7-4, START 30/18]
- Kaltenbach-Stipendium of the Deutsche Herzstiftung
Arrhythmogenic cardiomyopathy (AC) is an incurable genetic disease, whose pathogenesis is poorly understood. AC is characterized by arrhythmia, fibrosis, and cardiodilation that may lead to sudden cardiac death or heart failure. To elucidate AC pathogenesis and to design possible treatment strategies of AC, multiple murine models have been established. Among them, mice carrying desmoglein 2 mutations are particularly valuable given the identification of desmoglein 2 mutations in human AC and the detection of desmoglein 2 auto-antibodies in AC patients. Using two mouse strains producing either a mutant desmoglein 2 or lacking desmoglein 2 in cardiomyocytes, we test the hypothesis that inflammation is a major component of disease pathogenesis. We show that multifocal cardiomyocyte necrosis initiates a neutrophil-dominated inflammatory response, which also involves macrophages and T cells. Increased expression ofCcl2/Ccr2,Ccl3/Ccr5,andCxcl5/Cxcr2mRNA reflects the observed immune cell recruitment. During the ensuing acute disease phase,Mmp12(+)andSpp1(+) macrophages and T cells accumulate in scars, which mature from cell- to collagen-rich. The expression ofCx3cl1/Cx3cr1,Ccl2/Ccr2,andCxcl10/Cxcr3dominates this disease phase. We furthermore find that during chronic disease progression macrophages and T cells persist within mature scars and are present in expanding interstitial fibrosis.Ccl12andCx3cl1are predominant chemokines in this disease phase. Together, our observations provide strong evidence that specific immune cell populations and chemokine expression profiles modulate inflammatory and repair processes throughout AC progression.
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