EDIL3 deficiency ameliorates adverse cardiac remodelling by neutrophil extracellular traps (NET)-mediated macrophage polarization

Cardiovasc Res. 2022 Jul 20;118(9):2179-2195. doi: 10.1093/cvr/cvab269.

Abstract

Aims: After myocardial infarction (MI), injured cardiomyocytes recruit neutrophils and monocytes/macrophages to myocardium, which in turn initiates inflammatory and reparative cascades, respectively. Either insufficient or excessive inflammation impairs cardiac healing. As an endogenous inhibitor of neutrophil adhesion, EDIL3 plays a crucial role in inflammatory regulation. However, the role of EDIL3 in MI remains obscure. We aimed to define the role of EDIL3 in cardiac remodelling after MI.

Methods and results: Serum EDIL3 levels in MI patients were negatively associated with MI biomarkers. Consistently, WT mice after MI showed low levels of cardiac EDIL3. Compared with WT mice, Edil3-/- mice showed improvement of post-MI adverse remodelling, as they exhibited lower mortality, better cardiac function, shorter scar length, and smaller LV cavity. Accordingly, infarcted hearts of Edil3-/- mice contained fewer cellular debris and lower amounts of fibrosis content, with decreased collagen I/III expression and the percentage of α-smooth muscle actin myofibroblasts. Mechanistically, EDIL3 deficiency did not affect the recruitment of monocytes or T cells, but enhanced neutrophil recruitment and following expansion of pro-inflammatory Mertk-MHC-IIlo-int (myeloid-epithelial-reproductive tyrosine kinase/major histocompatibility complex II) macrophages. The injection of neutrophil-specific C-X-C motif chemokine receptor 2 antagonist eliminated the differences in macrophage polarization and cardiac function between WT and Edil3-/- mice after MI. Neutrophil extracellular traps (NETs), which were more abundant in the hearts of Edil3-/- mice, contributed to Mertk-MHC-IIlo-int polarization via Toll-like receptor 9 pathway. The inhibition of NET formation by treatment of neutrophil elastase inhibitor or DNase I impaired macrophage polarization, increased cellular debris and aggravated cardiac adverse remodelling, thus removed the differences of cardiac function between WT and Edil3-/- mice. Totally, EDIL3 plays an important role in NET-primed macrophage polarization and cardiac remodelling during MI.

Conclusion: We not only reveal that EDIL3 deficiency ameliorates adverse cardiac healing via NET-mediated pro-inflammatory macrophage polarization but also discover a new crosstalk between neutrophil and macrophage after MI.

Keywords: EDIL3; Fibrosis; Macrophages; Myocardial infarction; NETs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / blood
  • Calcium-Binding Proteins* / blood
  • Calcium-Binding Proteins* / deficiency
  • Calcium-Binding Proteins* / genetics
  • Calcium-Binding Proteins* / metabolism
  • Cell Adhesion Molecules* / blood
  • Cell Adhesion Molecules* / deficiency
  • Cell Adhesion Molecules* / genetics
  • Cell Adhesion Molecules* / metabolism
  • Extracellular Traps* / genetics
  • Extracellular Traps* / metabolism
  • Humans
  • Macrophages* / metabolism
  • Macrophages* / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardial Infarction* / blood
  • Myocardial Infarction* / metabolism
  • Myocardium / metabolism
  • Ventricular Remodeling* / genetics
  • Ventricular Remodeling* / physiology
  • c-Mer Tyrosine Kinase / metabolism

Substances

  • Biomarkers
  • Calcium-Binding Proteins
  • Cell Adhesion Molecules
  • EDIL3 protein, human
  • Edil3 protein, mouse
  • c-Mer Tyrosine Kinase