Accelerated Development of Pulmonary Fibrosis via Cu, Zn-superoxide Dismutase-induced Alternative Activation of Macrophages
Accelerated Development of Pulmonary Fibrosis via Cu, Zn-superoxide Dismutase-induced Alternative Activation of Macrophages
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DOI：
10.1074/jbc.m112.410720
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发表时间：
2013-07-12
影响因子：
4.8
通讯作者：
Carter, A. Brent
中科院分区：
文献类型：
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作者：
He, Chao;Ryan, Alan J.;Carter, A. Brent
巨噬细胞不仅在组织损伤后引发和加剧炎症，而且还参与消退和修复。巨噬细胞活性的这种差异是 M1 或 M2 表型分化过程的结果。 M1 巨噬细胞具有促炎性，具有杀菌和杀肿瘤活性，而 M2 巨噬细胞参与肿瘤进展和组织重塑，并且在某些条件下可以促纤维化。由于线粒体铜、锌超氧化物歧化酶 (Cu, Zn-SOD) 介导的 H2O2 对于肺纤维化的发展至关重要，因此我们假设铜、锌-SOD 调节巨噬细胞表型。在本研究中，我们证明 Cu、Zn-SOD 将巨噬细胞极化为 M2 表型，并且 Cu、Zn-SOD 介导的 H2O2 水平通过 STAT6 中关键半胱氨酸的氧化还原调节，在转录水平上调节 M2 基因表达。此外，小鼠体内 Cu、Zn-SOD 的过度表达会导致促纤维化环境并加速肺纤维化的发展，而巨噬细胞极化为 M1 表型则可减轻肺纤维化。总而言之，这些观察结果提供了 Cu、Zn-SOD 介导且不依赖 Th2 的 M2 极化的新机制，并为减缓肺纤维化的加速发展提供了潜在的治疗靶点。
Macrophages not only initiate and accentuate inflammation after tissue injury, but they are also involved in resolution and repair. This difference in macrophage activity is the result of a differentiation process to either M1 or M2 phenotypes. M1 macrophages are pro-inflammatory and have microbicidal and tumoricidal activity, whereas the M2 macrophages are involved in tumor progression and tissue remodeling and can be profibrotic in certain conditions. Because mitochondrial Cu, Zn-superoxide dismutase (Cu, Zn-SOD)-mediated H2O2 is crucial for development of pulmonary fibrosis, we hypothesized that Cu, Zn-SOD modulated the macrophage phenotype. In this study, we demonstrate that Cu, Zn-SOD polarized macrophages to an M2 phenotype, and Cu, Zn-SOD-mediated H2O2 levels modulated M2 gene expression at the transcriptional level by redox regulation of a critical cysteine in STAT6. Furthermore, overexpression of Cu, Zn-SOD in mice resulted in a profibrotic environment and accelerated the development of pulmonary fibrosis, whereas polarization of macrophages to the M1 phenotype attenuated pulmonary fibrosis. Taken together, these observations provide a novel mechanism of Cu, Zn-SOD-mediated and Th2-independent M2 polarization and provide a potential therapeutic target for attenuating the accelerated development of pulmonary fibrosis.