Foxp3+ CD4+ T Cells Improve Healing After Myocardial Infarction by Modulating monocyte/macrophage Differentiation

Circ Res. 2014 Jun 20;115(1):55-67. doi: 10.1161/CIRCRESAHA.115.303895. Epub 2014 Apr 30.

Abstract

Rationale: An exaggerated or persistent inflammatory activation after myocardial infarction (MI) leads to maladaptive healing and subsequent remodeling of the left ventricle. Foxp3(+) CD4(+) regulatory T cells (Treg cells) contribute to inflammation resolution. Therefore, Treg cells might influence cardiac healing post-MI.

Objective: Our aim was to study the functional role of Treg cells in wound healing post-MI in a mouse model of permanent left coronary artery ligation.

Methods and results: Using a model of genetic Treg-cell ablation (Foxp3(DTR) mice), we depleted the Treg-cell compartment before MI induction, resulting in aggravated cardiac inflammation and deteriorated clinical outcome. Mechanistically, Treg-cell depletion was associated with M1-like macrophage polarization, characterized by decreased expression of inflammation-resolving and healing-promoting factors. The phenotype of exacerbated cardiac inflammation and outcome in Treg-cell-ablated mice could be confirmed in a mouse model of anti-CD25 monoclonal antibody-mediated depletion. In contrast, therapeutic Treg-cell activation by superagonistic anti-CD28 monoclonal antibody administration 2 days after MI led to improved healing and survival. Compared with control animals, CD28-SA-treated mice showed increased collagen de novo expression within the scar, correlating with decreased rates of left ventricular ruptures. Therapeutic Treg-cell activation induced an M2-like macrophage differentiation within the healing myocardium, associated with myofibroblast activation and increased expression of monocyte/macrophage-derived proteins fostering wound healing.

Conclusions: Our data indicate that Treg cells beneficially influence wound healing after MI by modulating monocyte/macrophage differentiation. Moreover, therapeutic activation of Treg cells constitutes a novel approach to improve healing post-MI.

Keywords: myocardial infarction; wound healing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • Cell Polarity
  • Forkhead Transcription Factors / physiology*
  • Lymphocyte Activation
  • Macrophages / cytology*
  • Macrophages / physiology
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / cytology*
  • Myeloid Cells / physiology
  • Myocardial Infarction / immunology
  • Myocardial Infarction / physiopathology*
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / physiology*
  • Wound Healing*

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse