| First Author | Weirather J | Year | 2014 |
| Journal | Circ Res | Volume | 115 |
| Issue | 1 | Pages | 55-67 |
| PubMed ID | 24786398 | Mgi Jnum | J:249670 |
| Mgi Id | MGI:5920606 | Doi | 10.1161/CIRCRESAHA.115.303895 |
| Citation | Weirather J, et al. (2014) Foxp3+ CD4+ T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation. Circ Res 115(1):55-67 |
| abstractText | 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. |
