The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, South Korea.
Laboratory of Immune Network, Conversant Research Consortium in Immunologic disease, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
Sci Rep. 2016 Dec 23;6:39393. doi: 10.1038/srep39393.
Rheumatoid arthritis (RA) is an autoimmune disease that is related to the induction of T helper (Th)17 cells, which secrete interleukin-17, and activation of the signal transducer and activator of transcription (STAT) 3. The expression of high-temperature requirement protein A (HtrA) 2, a serine protease involved in apoptosis, was decreased in RA patients nonresponsive to drug treatment of RA. The aim of this study was to determine whether overexpression of HtrA2 has a therapeutic effect on RA. Th17 differentiation, osteoclastogenesis, and lymphocyte activation are increased in motor neuron degeneration (mnd)2 mice, which lack HtrA2 activity because of a missense mutation (Ser276Cys) in the protease domain of HtrA2. The inhibitor of HtrA2 also increased Th17 differentiation. On the other hand, HtrA2 induced cleavage of STAT3 and overexpression of HtrA2 attenuated CIA in a mouse model. HtrA2 overexpression inhibited plaque development as well as the differentiation of Th17 in ApoE mice after immunization with proteoglycans to induce a hyperlipidemia-based RA animal model. The therapeutic function of HtrA2 in inflammatory diseases is linked with Th17 development and the STAT3 pathway in splenocytes. These results suggest that HtrA2 participates in immunomodulatory activity where the upregulation of HtrA2 may shed light on therapeutic approaches to RA and hyperlipidemia.
类风湿关节炎（RA）是一种自身免疫性疾病，与辅助性 T 细胞（Th）17 细胞的诱导有关，Th17 细胞分泌白细胞介素-17，并激活信号转导和转录激活因子（STAT）3。在对 RA 药物治疗无反应的 RA 患者中，参与细胞凋亡的丝氨酸蛋白酶高迁移率族蛋白 A2（HtrA2）的表达降低。本研究旨在确定 HtrA2 的过表达是否对 RA 具有治疗作用。在运动神经元退行性变（mnd）2 小鼠中，Th17 分化、破骨细胞生成和淋巴细胞活化增加，mnd2 小鼠由于 HtrA2 蛋白酶结构域中的错义突变（Ser276Cys）而缺乏 HtrA2 活性。HtrA2 的抑制剂也增加了 Th17 分化。另一方面，HtrA2 诱导 STAT3 的裂解，而过表达 HtrA2 则可减轻 CIA 在小鼠模型中的作用。HtrA2 过表达可抑制斑块形成以及 ApoE 小鼠在免疫糖胺聚糖后 Th17 的分化，以诱导基于高脂血症的 RA 动物模型。HtrA2 在炎症性疾病中的治疗功能与 Th17 发育和脾细胞中的 STAT3 途径有关。这些结果表明，HtrA2 参与免疫调节活性，上调 HtrA2 可能为 RA 和高脂血症的治疗方法提供思路。
