Department of Periodontics, School of Dentistry, University of Texas Health Science Center San Antonio, San Antonio, Texas, USA.
Department of Developmental Dentistry, School of Dentistry, University of Texas Health Science Center San Antonio, San Antonio, Texas, USA.
Clin Transl Med. 2023 Apr;13(4):e1228. doi: 10.1002/ctm2.1228.
Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease that is embodied by the loss of salivary gland function and immune cell infiltration, but the mechanism(s) are still unknown. The aim of this study was to understand the mechanisms and identify key factors that leads to the development and progression of pSS.
Immunohistochemistry staining, FACS analysis and cytokine levels were used to detect immune cells infiltration and activation in salivary glands. RNA sequencing was performed to identify the molecular mechanisms involved in the development of pSS. The function assays include in vivo saliva collection along with calcium imaging and electrophysiology on isolated salivary gland cells in mice models of pSS. Western blotting, real-time PCR, alarmin release, and immunohistochemistry was performed to identify the channels involved in salivary function in pSS.
We provide evidence that loss of Ca signaling precedes a decrease in saliva secretion and/or immune cell infiltration in IL14α, a mouse model for pSS. We also showed that Ca homeostasis was mediated by transient receptor potential canonical-1 (TRPC1) channels and inhibition of TRPC1, resulting in the loss of salivary acinar cells, which promoted alarmin release essential for immune cell infiltration/release of pro-inflammatory cytokines. In addition, both IL14α and samples from human pSS patients showed a decrease in TRPC1 expression and increased acinar cell death. Finally, paquinimod treatment in IL14α restored Ca homeostasis that inhibited alarmin release thereby reverting the pSS phenotype.
These results indicate that loss of Ca signaling is one of the initial factors, which induces loss of salivary gland function along with immune infiltration that exaggerates pSS. Importantly, restoration of Ca signaling upon paquinimod treatment reversed the pSS phenotype thereby inhibiting the progressive development of pSS.
原发性干燥综合征（pSS）是一种系统性自身免疫性疾病，其特征为唾液腺功能丧失和免疫细胞浸润，但具体机制尚不清楚。本研究旨在了解导致 pSS 发生和进展的机制和关键因素。
采用免疫组织化学染色、FACS 分析和细胞因子水平检测唾液腺中免疫细胞浸润和活化。采用 RNA 测序鉴定 pSS 发生过程中涉及的分子机制。功能检测包括在 pSS 小鼠模型中进行体内唾液采集以及对分离的唾液腺细胞进行钙成像和电生理学检测。采用 Western blot、实时 PCR、警报素释放和免疫组织化学检测鉴定 pSS 中与唾液功能相关的通道。
我们提供的证据表明，在 IL14α小鼠模型中，钙信号的丧失先于唾液分泌减少和/或免疫细胞浸润，IL14α是 pSS 的一种小鼠模型。我们还表明，钙稳态由瞬时受体电位经典型-1（TRPC1）通道介导，TRPC1 的抑制导致唾液腺细胞的丧失，这促进了警报素的释放，警报素的释放对于免疫细胞浸润/促炎细胞因子的释放是必需的。此外，IL14α 和来自人类 pSS 患者的样本均显示 TRPC1 表达减少和腺泡细胞死亡增加。最后，帕奎莫德治疗 IL14α 恢复了钙稳态，抑制了警报素的释放，从而逆转了 pSS 表型。
这些结果表明，钙信号的丧失是导致唾液腺功能丧失和免疫浸润的最初因素之一，从而加重了 pSS。重要的是，帕奎莫德治疗后钙信号的恢复逆转了 pSS 表型，从而抑制了 pSS 的进行性发展。
