RORα 在原发性干燥综合征患者唾液腺病变中的作用。
The role of RORα in salivary gland lesions in patients with primary Sjögren's syndrome.
机构信息
Department of Stomatology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430071, Hubei Province, China.
Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Ave, Jianhan District, Wuhan, 430022, Hubei Province, China.
出版信息
Arthritis Res Ther. 2018 Sep 6;20(1):205. doi: 10.1186/s13075-018-1698-5.
BACKGROUND
The orphan nuclear receptors retinoic acid-related receptor α and γt (RORα and RORγt) are critical in the development of T helper 17 (Th17) cells, and ROR-specific synthetic ligands have proven efficacy in several mouse models of autoimmunity. However, the pathological significance of RORα in primary Sjögren's syndrome (pSS) remains to be elucidated. The present study was designed to clarify the significance of RORα in the pathogenesis of pSS.
METHODS
RORα expression in the labial salivary gland (LSG) was determined by immunohistochemical analysis using a quantitative scoring system in 34 patients with pSS. The correlation between RORα expression in LSGs and the focus score (FS) was determined, and Th17 and IL-17 receptor A (1L-17RA) levels in LSGs were determined. To investigate the effect of RORs and the therapeutic potential of targeting RORs in pSS, we administered SR1001, a selective RORα/γt inverse agonist, to non-obese diabetic (NOD) mice.
RESULTS
The expression of RORα was significantly increased in LSGs of patients with pSS and intensified with disease stage/FS, showing a similar increasing trend with IL-17A and IL-17RA. SR1001 significantly improved salivary gland secretory function and relieved sialadenitis in treated mice.
CONCLUSION
Our data reveal the importance of RORα in controlling pathologic lymphocytic infiltration of the salivary glands and suggest that RORα may be a druggable target in treating pSS.
背景
孤儿核受体维甲酸相关受体 α 和 γt（RORα 和 RORγt）在辅助性 T 细胞 17（Th17）细胞的发育中至关重要，并且 ROR 特异性合成配体已在几种自身免疫性疾病的小鼠模型中证明有效。然而，RORα 在原发性干燥综合征（pSS）中的病理意义仍有待阐明。本研究旨在阐明 RORα 在 pSS 发病机制中的意义。
方法
通过免疫组织化学分析，使用定量评分系统，在 34 例 pSS 患者的唇腺（LSG）中确定 RORα 的表达。确定 LSG 中 RORα 表达与焦点评分（FS）之间的相关性，并确定 LSG 中的 Th17 和白细胞介素-17 受体 A（IL-17RA）水平。为了研究 RORα 的作用以及靶向 RORα 在 pSS 中的治疗潜力，我们向非肥胖型糖尿病（NOD）小鼠给予了 RORα/γt 反向激动剂 SR1001。
结果
RORα 在 pSS 患者的 LSG 中的表达显著增加，并随疾病阶段/FS 而增强，与 IL-17A 和 IL-17RA 呈相似的递增趋势。SR1001 显著改善了唾液腺的分泌功能并缓解了治疗小鼠的涎腺炎。
结论
我们的数据揭示了 RORα 在控制唾液腺病理性淋巴细胞浸润中的重要性，并表明 RORα 可能是治疗 pSS 的可靶向治疗靶点。
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