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Inflammation shapes pathogenesis of murine arrhythmogenic cardiomyopathy

Nadine Lubos1, Svenja van der Gaag1, Muhammed Gerçek1

  • 1Institute of Molecular and Cellular Anatomy, RWTH Aachen University, 52074, Aachen, Germany.

Basic Research in Cardiology
|June 13, 2020
PubMed

Insights

Inflammation drives arrhythmogenic cardiomyopathy (AC) progression. Immune cells like neutrophils, macrophages, and T cells, along with specific chemokines, play key roles in AC pathogenesis and scar development.

Area of Science:

  • Cardiovascular Research
  • Immunology
  • Genetic Diseases

Background:

  • Arrhythmogenic cardiomyopathy (AC) is an incurable genetic heart disease characterized by arrhythmia, fibrosis, and dilation, often leading to sudden cardiac death or heart failure.
  • The precise pathogenesis of AC remains poorly understood, necessitating the development of effective therapeutic strategies.
  • Desmoglein 2 (DSG2) mutations are linked to human AC, and DSG2 auto-antibodies are found in patients, making DSG2-related mouse models crucial for research.

Purpose of the Study:

  • To investigate the role of inflammation in the pathogenesis of arrhythmogenic cardiomyopathy (AC).
  • To elucidate the specific immune cell populations and chemokine profiles involved in AC progression.
  • To explore potential therapeutic targets by understanding the inflammatory mechanisms in AC.

Main Methods:

  • Utilized two mouse strains: one with mutant desmoglein 2 (DSG2) and another lacking DSG2 in cardiomyocytes.
  • Analyzed inflammatory responses, including cardiomyocyte necrosis, immune cell infiltration (neutrophils, macrophages, T cells), and chemokine expression (Ccl2/Ccr2, Ccl3/Ccr5, Cxcl5/Cxcr2, Cx3cl1/Cx3cr1, Cxcl10/Cxcr3).
  • Examined scar formation and progression from cellular to collagen-rich structures during acute and chronic disease phases.

Main Results:

  • Multifocal cardiomyocyte necrosis initiated neutrophil-dominated inflammation, involving macrophages and T cells.
  • Acute phase showed accumulation of Mmp12+ and Spp1+ macrophages and T cells in developing scars, with dominant chemokine expression of Cx3cl1/Cx3cr1, Ccl2/Ccr2, and Cxcl10/Cxcr3.
  • Chronic phase revealed persistent macrophages and T cells in mature scars and expanding fibrosis, with Ccl12 and Cx3cl1 as predominant chemokines.

Conclusions:

  • Inflammation, driven by specific immune cell populations and chemokine signaling, is a major component of arrhythmogenic cardiomyopathy pathogenesis.
  • Immune cell dynamics and chemokine expression profiles evolve throughout AC progression, influencing inflammatory and repair processes.
  • These findings highlight the potential of targeting inflammatory pathways and immune cell interactions for AC treatment.

Keywords:
CardiomyopathyChronic disease progressionDesmogleinDesmosomeImmune cellsInflammation

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