Foxp3+ CD4+ T Cells Improve Healing After Myocardial Infarction by Modulating Monocyte/Macrophage Differentiation

J Weirather, UDW Hofmann, N Beyersdorf… - Circulation …, 2014 - Am Heart Assoc
J Weirather, UDW Hofmann, N Beyersdorf, GC Ramos, B Vogel, A Frey, G Ertl, T Kerkau…
Circulation research, 2014Am Heart Assoc
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 (Foxp3DTR …
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 (Foxp3DTR 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.
Am Heart Assoc