高温需求丝氨酸蛋白酶 A2 在类风湿性炎症中的作用。

Role of high-temperature requirement serine protease A 2 in rheumatoid inflammation.

机构信息

Department of Biomedicine & Health Sciences, Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Center for Integrative Rheumatoid Transcriptomics and Dynamics, The Catholic University of Korea, Seoul, Korea.

出版信息

Arthritis Res Ther. 2023 Jun 7;25(1):96. doi: 10.1186/s13075-023-03081-z.

DOI:10.1186/s13075-023-03081-z

PMID:37287073

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10246393/

Abstract

BACKGROUND

High-temperature requirement serine protease A 2 (HtrA2) is known to be involved in growth, unfolded protein response to stress, apoptosis, and autophagy. However, whether HtrA2 controls inflammation and immune response remains elusive.

METHODS

Expression of HtrA2 in the synovial tissue of patients was examined using immunohistochemistry and immunofluorescence staining. Enzyme-linked immunosorbent assay was used to determine the concentrations of HtrA2, interleukin-6 (IL-6), interleukin-8 (IL-8), chemokine (C-C motif) ligand 2 (CCL2), and tumor necrosis factor α (TNFα). Synoviocyte survival was assessed by MTT assay. For the downregulation of HtrA2 transcripts, cells were transfected with HtrA2 siRNA.

RESULTS

We found that the concentration of HtrA2 was elevated in rheumatoid arthritis (RA) synovial fluid (SF) than in osteoarthritis (OA) SF, and its concentrations were correlated with the number of immune cells in the RA SF. Interestingly, HtrA2 levels in the SF of RA patients were elevated in proportion to synovitis severity and correlated with the expression of proinflammation cytokines and chemokines, such as IL-6, IL-8, and CCL2. In addition, HtrA2 was highly expressed in RA synovium and primary synoviocytes. RA synoviocytes released HtrA2 when stimulated with ER stress inducers. Knockdown of HtrA2 inhibited the IL1β-, TNFα-, and LPS-induced release of proinflammatory cytokines and chemokines by RA synoviocytes.

CONCLUSION

HtrA2 is a novel inflammatory mediator and a potential target for the development of an anti-inflammation therapy for RA.

摘要

背景

高温需求丝氨酸蛋白酶 A2（HtrA2）已知参与生长、应激未折叠蛋白反应、细胞凋亡和自噬。然而，HtrA2 是否控制炎症和免疫反应仍不清楚。

方法

使用免疫组织化学和免疫荧光染色检查 HtrA2 在患者滑膜组织中的表达。酶联免疫吸附试验用于测定 HtrA2、白细胞介素 6（IL-6）、白细胞介素 8（IL-8）、趋化因子（C-C 基序）配体 2（CCL2）和肿瘤坏死因子α（TNFα）的浓度。通过 MTT 测定评估滑膜细胞的存活率。为了下调 HtrA2 转录本，用 HtrA2 siRNA 转染细胞。

结果

我们发现类风湿关节炎（RA）滑液（SF）中的 HtrA2 浓度高于骨关节炎（OA）SF，其浓度与 RA SF 中免疫细胞的数量相关。有趣的是，RA 患者 SF 中的 HtrA2 水平与滑膜炎严重程度成正比，并与促炎细胞因子和趋化因子（如 IL-6、IL-8 和 CCL2）的表达相关。此外，HtrA2 在 RA 滑膜和原代滑膜细胞中高表达。RA 滑膜细胞在 ER 应激诱导剂刺激下释放 HtrA2。敲低 HtrA2 抑制了 RA 滑膜细胞中由 IL1β、TNFα 和 LPS 诱导的促炎细胞因子和趋化因子的释放。