Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, 230032 Anhui, China.
Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei, 230032 Anhui, China.
Int Immunopharmacol. 2021 Dec;101(Pt A):108281. doi: 10.1016/j.intimp.2021.108281. Epub 2021 Oct 29.
The etiology of primary Sjögren's syndrome (pSS) remains unknown, and there is no ideal drug for the specific treatment of pSS. β-arrestin2 is a key protein that mediates desensitization and internalization of G protein-coupled receptors (GPCRs) and it participates in inflammatory and immune responses that have been found to mediate apoptosis in autoimmune disease. In this study, we established an experimental Sjögren's syndrome (ESS) mouse model to elucidate the molecular mechanisms of β-arrestin2 in pSS. First, excessive activation of β-arrestin2 and GRP78-ATF6-CHOP apoptosis signaling were detected in specimens from pSS patients. In vivo, we found that inhibition of GRP78-ATF6-CHOP apoptosis signaling improved ESS symptoms, and the targeted deletion of β-arrestin2 significantly increased saliva flow, alleviated salivary gland indices, and improved tissue integrity in the ESS model by downregulating GRP78-ATF6-CHOP apoptosis signaling. In vitro, we used IFNα to stimulate human salivary gland epithelial cells (HSGECs), and the results showed that IFNα activated GRP78-ATF6-CHOP apoptosis signaling, decreased cell viability, and induced apoptosis, which were negatively regulated by the ERS inhibitor 4-PBA. In addition, β-arrestin2 depletion downregulated GRP78-ATF6-CHOP apoptosis signaling to alleviate cell apoptosis, and the effect depended on the interaction between GRP78 and β-arrestin2. In summary, our results suggest that excessive activation of GRP78-ATF6-CHOP apoptosis signaling is involved in the pathogenesis of pSS and that β-arrestin2 encourages inflammation-induced epithelial apoptosis through GRP78-ATF6-CHOP apoptosis signaling. This research further clarified the underlying role of β-arrestin2 and provided an experimental foundation for β-arrestin2 depletion in the treatment of the human autoimmune disorder pSS.
原发性干燥综合征（pSS）的病因尚不清楚，也没有针对 pSS 的特效治疗药物。β-arrestin2 是一种关键蛋白，可介导 G 蛋白偶联受体（GPCR）的脱敏和内化，它参与炎症和免疫反应，这些反应已被发现可介导自身免疫性疾病中的细胞凋亡。在这项研究中，我们建立了实验性干燥综合征（ESS）小鼠模型，以阐明β-arrestin2 在 pSS 中的分子机制。首先，在 pSS 患者的标本中检测到β-arrestin2 的过度激活和 GRP78-ATF6-CHOP 凋亡信号。在体内，我们发现抑制 GRP78-ATF6-CHOP 凋亡信号可改善 ESS 症状，而通过下调 GRP78-ATF6-CHOP 凋亡信号，β-arrestin2 的靶向缺失可显著增加唾液流量、减轻唾液腺指数，并改善 ESS 模型中的组织完整性。在体外，我们使用 IFNα 刺激人唾液腺上皮细胞（HSGECs），结果表明 IFNα 激活了 GRP78-ATF6-CHOP 凋亡信号，降低了细胞活力并诱导了细胞凋亡，而内质网应激抑制剂 4-PBA 可对此进行负调控。此外，β-arrestin2 的缺失下调了 GRP78-ATF6-CHOP 凋亡信号，从而减轻了细胞凋亡，而这种作用取决于 GRP78 与β-arrestin2 之间的相互作用。总之，我们的结果表明，GRP78-ATF6-CHOP 凋亡信号的过度激活参与了 pSS 的发病机制，而β-arrestin2 通过 GRP78-ATF6-CHOP 凋亡信号促进炎症诱导的上皮细胞凋亡。这项研究进一步阐明了β-arrestin2 的潜在作用，并为β-arrestin2 缺失在治疗人类自身免疫性疾病 pSS 方面提供了实验基础。
