Foxp3+ CD4+ T 细胞通过调节单核细胞/巨噬细胞分化来改善心肌梗死后的愈合。
Foxp3+ CD4+ T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation.
机构信息
From the Department of Internal Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany (J.W., U.H., G.C.R., B.V, A.F., G.E., S.F.); and Department of Immunobiology (N.B., T.K.), and Comprehensive Heart Failure Center (J.W., U.H., G.C.R., B.V., A.F., G.E., S.F.), University of Wuerzburg, Wuerzburg, Germany.
出版信息
Circ Res. 2014 Jun 20;115(1):55-67. doi: 10.1161/CIRCRESAHA.115.303895. Epub 2014 Apr 30.
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.
背景
心肌梗死后（MI）炎症过度或持续激活会导致左心室适应不良愈合和随后的重塑。Foxp3(+)CD4(+)调节性 T 细胞（Treg 细胞）有助于炎症消退。因此，Treg 细胞可能会影响 MI 后的心脏愈合。
目的
我们的目的是在永久性左冠状动脉结扎的小鼠模型中研究 Treg 细胞在 MI 后伤口愈合中的功能作用。
方法和结果
我们使用 Treg 细胞耗竭模型（Foxp3(DTR) 小鼠），在 MI 诱导前耗竭 Treg 细胞，导致心脏炎症加重和临床结局恶化。从机制上讲，Treg 细胞耗竭与 M1 样巨噬细胞极化有关，其特征是炎症消退和促进愈合的因子表达减少。在 Treg 细胞耗竭的小鼠模型中，可证实心脏炎症加剧和结局恶化的表型。相反，MI 后 2 天给予超激动性抗 CD28 单克隆抗体治疗可激活 Treg 细胞，从而改善愈合和生存。与对照组相比，CD28-SA 治疗组在疤痕内新表达的胶原增加，与左心室破裂率降低相关。治疗性 Treg 细胞激活可诱导愈合心肌内 M2 样巨噬细胞分化，与成肌纤维细胞激活和增加表达促进伤口愈合的单核细胞/巨噬细胞衍生蛋白相关。
结论
我们的数据表明，Treg 细胞通过调节单核细胞/巨噬细胞分化对 MI 后伤口愈合有益。此外，Treg 细胞的治疗性激活是改善 MI 后愈合的一种新方法。
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