Laboratory of Dermato-Immunology, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University, Seoul, Republic of Korea.
Antioxid Redox Signal. 2012 Nov 15;17(10):1376-92. doi: 10.1089/ars.2012.4572. Epub 2012 Jun 29.
The extracellular superoxide dismutase 3 (SOD3) is an isoform of SOD. Extensive studies have been focused on role of SOD3 as an antioxidant. However, the role of SOD3 in the immune responses that contribute to the inhibition of allergic lung inflammation has not been investigated.
Here, we report for the first time that SOD3 specifically inhibits dendritic cell maturation. Subsequently, SOD3 controls T cell activation and proliferation, and T helper 2 (Th2) and Th17 cell differentiation. As a consequence, the administration of SOD3 into mice alleviated Th2-cell-mediated ovalbumin (OVA)-induced allergic asthma. In addition, we demonstrated that SOD3 inhibits OVA-induced airway extracellular remodeling and Th2 cell trafficking. Through mass spectrometry analysis, the proteins interacting with SOD3 in the lung of asthma were identified. And it was revealed that signaling molecules, such as transforming growth factor (TGF) and epidermal growth factor (EGF) receptor, adhesion and adaptor molecules, kinases, phosphatases, NADPH oxidase, and apoptosis-related factor, were involved, which were altered by administration of SOD3. Relatively severe asthma was observed in SOD3 KO mice and was ameliorated by both the administration of SOD3 and adoptive transfer of SOD3-sufficient CD4 T cells. Moreover, the expression of endogenous SOD3 in the lung peaked early in OVA challenge and gradually decreased upon disease progression, while both SOD1 and SOD2 expression changed relatively little.
Thus, our data suggest that SOD3 is required to maintain lung homeostasis and acts, at least in part, as a controller of signaling and a decision maker to determine the progression of allergic lung disease.
细胞外超氧化物歧化酶 3（SOD3）是 SOD 的同工酶。大量研究集中在 SOD3 作为抗氧化剂的作用上。然而，SOD3 在有助于抑制过敏性肺炎症的免疫反应中的作用尚未得到研究。
在这里，我们首次报道 SOD3 特异性抑制树突状细胞成熟。随后，SOD3 控制 T 细胞激活和增殖，以及辅助性 T 细胞 2（Th2）和 Th17 细胞分化。因此，将 SOD3 给药到小鼠体内缓解了 Th2 细胞介导的卵清蛋白（OVA）诱导的过敏性哮喘。此外，我们证明 SOD3 抑制 OVA 诱导的气道细胞外重塑和 Th2 细胞迁移。通过质谱分析，鉴定了哮喘患者肺部与 SOD3 相互作用的蛋白质。结果表明，转化生长因子（TGF）和表皮生长因子（EGF）受体等信号分子、黏附分子和衔接分子、激酶、磷酸酶、NADPH 氧化酶和凋亡相关因子参与其中，这些分子的活性被 SOD3 调节。SOD3 敲除小鼠中观察到相对严重的哮喘，并且通过 SOD3 给药和过继转移 SOD3 充足的 CD4 T 细胞均可改善。此外，在 OVA 挑战中，肺部内源性 SOD3 的表达在早期达到峰值，并在疾病进展过程中逐渐下降，而 SOD1 和 SOD2 的表达变化相对较小。
因此，我们的数据表明 SOD3 是维持肺内稳态所必需的，至少部分地作为信号转导的控制器和决定过敏性肺疾病进展的决策者发挥作用。
