Accelerated Development of Pulmonary Fibrosis via Cu, Zn-superoxide Dismutase-induced Alternative Activation of Macrophages

作者：He Chao; Ryan Alan J; Murthy Shubha; Carter A Brent^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2013, 288(28): 20745-20757.

DOI：10.1074/jbc.M112.410720

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.

• 出版日期2013-7-12