Institute for Immunobiology, Shanghai Medical College, Fudan University, Shanghai, P. R. China.
PLoS One. 2013 Sep 4;8(9):e74955. doi: 10.1371/journal.pone.0074955. eCollection 2013.
Cardiac fibrogenesis in the late stage of viral myocarditis causing contractile dysfunction and ventricular dilatation, is a major pathogenic factor for the progression of myocarditis to serious cardiovascular diseases including dilated cardiomyopathy (DCM) and congestive heart failure (HF). Recent studies indicate that regulatory T cells (Tregs) are involved in the fibrotic process of liver and lung fibosis. However, the role of Tregs in the development of viral myocarditis-caused cardiac fibrosis and their therapeutic potential remains unclear.
METHODOLOGY/PRINCIPAL FINDINGS: Myocardial fibrosis was induced in BALB/c mice by intraperitoneal injection of Coxsackievirus B3 (CVB3) assessed by picrosirius red staining and detection of expression levels of collagen I, matrix metalloproteinase-1 (MMP-1), matrix metalloproteinase-3 (MMP-3) and tissue inhibitor of metalloproteinase-1 (TIMP-1). Myocardial Treg frequency was down-regulated during the course of viral myocarditis and a negative correlation with the severity of cardiac fibrosis was found. To explore the role of Tregs in CVB-induced cardiac fibrosis, Treg was in vivo depleted by injecting anti-CD25 mAb which resulted in aggravation of cardiac fibrosis. In consistent with that, after adoptive transfer of isolated Tregs into mice, significant amelioration of CVB3-induced cardiac fibrosis was confirmed. Interleukin-10 (IL-10) neutralizing antibodies were used in vivo and in vitro to explore the molecular mechanism of the therapeutic effect of Treg. It was found that administration of anti-IL-10 mAb after Treg transfer abrogated Treg's treating effect and the inhibition of Treg on collagen production by cardiac fibroblasts was mediated mainly through IL-10.
CONCLUSION/SIGNIFICANCE: Our data suggested that Tregs have a protective role in the fibrotic process of CVB3-induced cardiac fibrosis via secreting IL-10 and might provide an alternative option for the future treatment of cardiac fibrosis.
病毒性心肌炎晚期的心肌纤维化导致收缩功能障碍和心室扩张，是心肌炎进展为严重心血管疾病（包括扩张型心肌病 [DCM] 和充血性心力衰竭 [HF]）的主要致病因素。最近的研究表明，调节性 T 细胞（Tregs）参与了肝纤维化和肺纤维化的纤维化过程。然而，Tregs 在病毒性心肌炎引起的心肌纤维化发展中的作用及其治疗潜力尚不清楚。
方法/主要发现：通过 Picrosirius 红染色和检测胶原 I、基质金属蛋白酶-1（MMP-1）、基质金属蛋白酶-3（MMP-3）和金属蛋白酶组织抑制剂-1（TIMP-1）的表达水平，评估 BALB/c 小鼠腹腔注射柯萨奇病毒 B3（CVB3）诱导的心肌纤维化。在病毒性心肌炎过程中，心肌 Treg 频率下调，与心肌纤维化的严重程度呈负相关。为了探讨 Tregs 在 CVB 诱导的心肌纤维化中的作用，通过注射抗 CD25 mAb 体内耗竭 Treg，导致心肌纤维化加重。与这一结果一致的是，将分离的 Tregs 过继转移到小鼠体内后，证实了 CVB3 诱导的心肌纤维化的显著改善。体内和体外均使用白细胞介素-10（IL-10）中和抗体来探讨 Treg 治疗作用的分子机制。结果发现，Treg 转移后给予抗 IL-10 mAb 可消除 Treg 的治疗作用，Treg 对心肌成纤维细胞胶原产生的抑制作用主要通过 IL-10 介导。
结论/意义：我们的数据表明，Tregs 通过分泌 IL-10 在 CVB3 诱导的心肌纤维化的纤维化过程中具有保护作用，可能为未来的心肌纤维化治疗提供一种替代选择。
