Foxp3+CD4+ T Cells Improve Healing after Myocardial Infarction by Modulating Monocyte/Macrophage Differentiation
Rationale: An exaggerated or persistent inflammatory activation after myocardial infarction (MI) leads to maladaptive healing and subsequent remodeling of the left ventricle. CD4+Foxp3+ regulatory T cells (Treg cells) contribute to inflammation resolution. Therefore, Treg cells might influence cardiac healing post-MI.
Objective: To study the functional role of Treg cells for 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 (Foxp3DTR mice), we depleted the Foxp3+ 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 to 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" monocyte 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.
- Received March 14, 2014.
- Revision received April 24, 2014.
- Accepted April 30, 2014.