Department of Emergency Medicine and Critical Care, Shanghai East Hospital, Tong Ji University, Shanghai, China.
Dalian Medical University, Liaoning, China.
Shock. 2018 Oct;50(4):455-464. doi: 10.1097/SHK.0000000000001070.
We recently reported that CD4CD25 regulatory T cells (Tregs) contributed to the recovery of patients with acute lung injury (ALI) by upregulating T cell immunoglobulin and mucin-domain containing-3 (Tim-3). However, the molecular mechanism by which Tim-3 regulates Tregs' function in the resolution and fibroproliferation after ALI remains unknown. In this study, we adoptively transferred Tim-3Tregs or Tim-3Tregs into lipopolysaccharide -induced ALI mice model. Data demonstrated that Tim-3Tregs not only decreased indices of lung inflammation and injury but also mitigated lung fibrosis after ALI. Furthermore, we observed that the transfer of Tim-3Tregs led to M2-like macrophage differentiation as demonstrated by significantly upregulated levels of M2-associated phenotypic markers as well as downregulated expressions of M1-related markers in both the profibrotic lung tissue and sorted pulmonary monocytes after ALI. In addition, cytokines such as interleukin (IL)-10 and IL-4 were also upregulated in lung tissues after Tim-3Tregs transferring. In vitro experiments further demonstrated that cell-contact cocultures with Tregs lacking Tim-3 presented decreased polarization of M2-like macrophages partially mediated by a decreased expression and function of STAT-3. Therefore, these data demonstrate a previously unrecognized function of Tim-3 on Tregs in their ability to repress the fibroproliferation of ALI by inducing alternative macrophages polarization. Moreover, the data highlight that Tim-3Tregs-mediated induction of M2-like macrophages may be a novel treatment modality with transitional potential.
我们最近报道称，CD4+CD25+调节性 T 细胞（Tregs）通过上调 T 细胞免疫球蛋白和粘蛋白结构域 3（Tim-3）促进急性肺损伤（ALI）患者的恢复。然而，Tim-3 调节 Tregs 在 ALI 后恢复和纤维化过程中功能的分子机制尚不清楚。在这项研究中，我们过继转移 Tim-3+Tregs 或 Tim-3+Tregs 到脂多糖诱导的 ALI 小鼠模型中。数据表明，Tim-3+Tregs 不仅降低了肺炎症和损伤的指标，而且减轻了 ALI 后的肺纤维化。此外，我们观察到，Tim-3+Tregs 的转移导致 M2 样巨噬细胞分化，这表现为 M2 相关表型标志物的水平显著上调，以及 M1 相关标志物在 ALI 后纤维化肺组织和分选的肺单核细胞中的表达下调。此外，IL-10 和 IL-4 等细胞因子在 Tim-3+Tregs 转移后肺组织中也上调。体外实验进一步表明，与缺乏 Tim-3 的 Tregs 进行细胞接触共培养时，M2 样巨噬细胞的极化程度降低，部分原因是 STAT-3 的表达和功能降低。因此，这些数据表明，Tim-3 在 Tregs 抑制 ALI 纤维化增殖的能力上具有以前未被认识的功能，通过诱导替代型巨噬细胞极化。此外，这些数据突出表明，Tim-3+Tregs 诱导的 M2 样巨噬细胞可能是一种具有过渡潜力的新型治疗方法。
