Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea.
Exp Lung Res. 2021 Dec;47(10):465-475. doi: 10.1080/01902148.2021.1998733. Epub 2021 Nov 24.
Transforming growth factor beta 1 (TGF-β1) induces pulmonary fibrosis by enhancing epithelial apoptosis and affects the enzymatic activity of transglutaminase 2 (TG2). The aim of this study was to determine the role of TG2 in TGF-β1-induced lung remodeling and alveolar macrophage modulation. We characterized the o effects of TGF-β1 and TG2 on lung inflammation, fibrosis, and macrophage activity using transgenic C57BL/6 mice with wild and null TG2 loci. The effect of TG2 inhibition on TGF-β1-stimulated alveolar macrophages was assessed through mRNA analysis. TG2 was remarkably upregulated in the lungs of TGF-β1 transgenic (TGF-β1 Tg) mice, especially in alveolar macrophages and epithelial cells. In the absence of TG2, TGF-β1-induced inflammation was suppressed, decreasing the number of macrophages in the bronchoalveolar lavage fluid. In addition, the alveolar destruction and peribronchial fibrosis induced by TGF-β1 overexpression were significantly reduced, which correlated with decreases in the expression of fibroblast growth factor and matrix metallopeptidase 12, respectively. However, TG2 deficiency did not compromise the phagocytic activity of alveolar macrophages in TGF-β1 Tg mice. At the same time, TG2 contributed to the regulation of TGF-β1-induced macrophage activation. Inhibition of TG2 did not affect the TGF-β1-induced expression of CD86, an M1 marker, in macrophages, but it did reverse the TGF-β1-induced expression of CD206. This result suggests that TG2 mediates TGF-β1-induced M2-like polarization but does not contribute to TGF-β1-induced M1 polarization. In conclusion, TG2 regulates macrophage modulation and plays an important role in TGF-β1-induced lung inflammation, destruction, and fibrosis.
转化生长因子β 1（TGF-β1）通过增强上皮细胞凋亡来诱导肺纤维化，并影响转谷氨酰胺酶 2（TG2）的酶活性。本研究旨在确定 TG2 在 TGF-β1 诱导的肺重塑和肺泡巨噬细胞调节中的作用。我们使用具有野生和缺失 TG2 基因座的转基因 C57BL/6 小鼠，表征了 TGF-β1 和 TG2 对肺炎症、纤维化和巨噬细胞活性的影响。通过 mRNA 分析评估了 TG2 抑制对 TGF-β1 刺激的肺泡巨噬细胞的影响。TGF-β1 转基因（TGF-β1Tg）小鼠的肺中 TG2 显著上调，特别是在肺泡巨噬细胞和上皮细胞中。在没有 TG2 的情况下，抑制 TGF-β1 诱导的炎症反应，减少支气管肺泡灌洗液中的巨噬细胞数量。此外，TGF-β1 过表达诱导的肺泡破坏和支气管周围纤维化明显减少，分别与成纤维细胞生长因子和基质金属蛋白酶 12 的表达减少相关。然而，TG2 缺失并不影响 TGF-β1Tg 小鼠肺泡巨噬细胞的吞噬活性。同时，TG2 有助于调节 TGF-β1 诱导的巨噬细胞活化。TG2 抑制不影响 TGF-β1 诱导的巨噬细胞中 M1 标志物 CD86 的表达，但逆转了 TGF-β1 诱导的 CD206 表达。这一结果表明，TG2 介导 TGF-β1 诱导的 M2 样极化，但不促进 TGF-β1 诱导的 M1 极化。总之，TG2 调节巨噬细胞调节，在 TGF-β1 诱导的肺炎症、破坏和纤维化中发挥重要作用。
