Cu,Zn-Superoxide Dismutase-Mediated Redox Regulation of Jumonji Domain Containing 3 Modulates Macrophage Polarization and Pulmonary Fibrosis
Cu,Zn-Superoxide Dismutase-Mediated Redox Regulation of Jumonji Domain Containing 3 Modulates Macrophage Polarization and Pulmonary Fibrosis
复制标题
DOI：
10.1165/rcmb.2015-0183oc
复制
发表时间：
2016-07-01
影响因子：
6.4
通讯作者：
Carter, A. Brent
中科院分区：
文献类型：
--
作者：
He, Chao;Larson-Casey, Jennifer L.;Carter, A. Brent
M2巨噬细胞产生促纤维化信号，参与肺纤维化的发展。极化过程，至少部分是由表观遗传调节调节的。由于Cu， zn -超氧化物歧化酶诱导的H2O2可以使巨噬细胞极化为纤维化的M2表型，我们假设细胞氧化还原状态的调节参与了巨噬细胞表型的表观遗传调节。在这项研究中，我们发现信号换能器和转录激活因子6 （STAT6）调节含Jumonji结构域（Jmjd） 3，一种组蛋白H3 lysine 27去甲基化酶，STAT6中氧化还原敏感半胱氨酸的突变会减弱jmjd3的表达。此外，Jmjd3缺乏可消除促纤维化M2基因的表达。来氟米特治疗可以减少线粒体活性氧的产生和酪氨酸磷酸化，抑制jmjd3的表达和M2极化，以及纤维化表型的发展。综上所述，这些观察结果证明Jmjd3的氧化还原调控是Cu， zn -超氧化物歧化酶介导的促纤维化M2极化的独特调控机制。此外，来氟米特可以减少活性氧的产生和酪氨酸磷酸化，可能被证明在治疗石棉引起的肺纤维化方面具有治疗作用。
M2 macrophages are implicated in the development of pulmonary fibrosis as they generate profibrotic signals. The polarization process, at least in part, is regulated by epigenetic modulation. Because Cu,Zn-superoxide dismutase-induced H2O2 can polarize macrophages to a profibrotic M2 phenotype, we hypothesized that modulation of the redox state of the cell is involved in the epigenetic modulation of the macrophage phenotype. In this study, we show that signal transducer and activator of transcription 6 (STAT6) regulates Jumonji domain containing (Jmjd) 3, a histone H3 lysine 27 demethylase, and mutation of a redox-sensitive cysteine in STAT6 attenuates jmjd3 expression. Moreover, Jmjd3 deficiency abrogates profibrotic M2 gene expression. Treatment with leflunomide, which reduces mitochondrial reactive oxygen species production and tyrosine phosphorylation, inhibits jmjd3 expression and M2 polarization, as well as development of a fibrotic phenotype. Taken together, these observations provide evidence that the redox regulation of Jmjd3 is a unique regulatory mechanism for Cu,Zn-superoxide dismutase-mediated profibrotic M2 polarization. Furthermore, leflunomide, which reduces reactive oxygen species production and tyrosine phosphorylation, may prove to be therapeutic in the treatment of asbestos-induced pulmonary fibrosis.