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

• Published in: The Journal of biological chemistry Vol. 288; no. 28; pp. 20745 - 20757
• Main Authors: He, Chao, Ryan, Alan J., Murthy, Shubha, Carter, A. Brent
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.07.2013; American Society for Biochemistry and Molecular Biology
• Subjects: Adolescent; Adult; Animals; Cell Line; Cell Polarity - genetics; Cytokines - genetics; Cytokines - metabolism; Disease Progression; Gene Expression; Humans; Hydrogen Peroxide; Hydrogen Peroxide - metabolism; Immunoblotting; Macrophage Activation - genetics; Macrophage Phenotype; Macrophages - classification; Macrophages - enzymology; Macrophages - metabolism; Macrophages, Alveolar - classification; Macrophages, Alveolar - enzymology; Macrophages, Alveolar - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Middle Aged; Mitochondria; Mitochondria - enzymology; Mitochondria - genetics; Mitochondria - metabolism; Molecular Bases of Disease; Oxidative Stress; Pulmonary Fibrosis; Pulmonary Fibrosis - genetics; Pulmonary Fibrosis - metabolism; Pulmonary Fibrosis - pathology; Reverse Transcriptase Polymerase Chain Reaction; STAT6; Superoxide Dismutase (SOD); Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Th2 Cells - metabolism; Young Adult; Mitochondria; Oxidative Stress; Superoxide Dismutase (SOD); Hydrogen Peroxide; Macrophage Phenotype; Pulmonary Fibrosis; STAT6
• ISSN: 0021-9258; 1083-351X
• 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. Background: Macrophages play an important role in inflammation and injury as well as resolution of the response. Results: Mitochondrial Cu,Zn-SOD-mediated H2O2 polarizes macrophages to an M2 phenotype. Conclusion: A prolonged predominance of M2 macrophages can induce a fibrotic phenotype. Significance: The antioxidant enzyme, Cu,Zn-SOD, increases mitochondrial H2O2 levels, which is linked to pulmonary fibrosis.