Facultad de Odontología, Universidad San Sebastián, Santiago, Chile.
Clínica INDISA, Santiago, Chile.
Rheumatology (Oxford). 2021 Apr 6;60(4):1951-1962. doi: 10.1093/rheumatology/keaa670.
Altered homeostasis of salivary gland (SG) epithelial cells in Sjögren's syndrome (SS) could be the initiating factor that leads to inflammation, secretory dysfunction and autoimmunity. Autophagy is an important homeostatic mechanism, whose deficiency is associated with inflammation and accumulation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) components. We aimed to evaluate whether autophagy is altered in labial SG (LSG) epithelial cells from primary SS (pSS) patients and whether this contributes to inflammation through the JAK-STAT pathway. Furthermore, we investigated the anti-inflammatory effect of the JAK inhibitor tofacitinib in autophagy-deficient (ATG5 knockdown) three-dimensional (3D)-acini.
We analysed LSG biopsies from 12 pSS patients with low focus score and 10 controls. ATG5-deficient 3D-acini were generated and incubated with IL-6 in the presence or absence of tofacitinib. Autophagy markers, pro-inflammatory cytokine expression, and JAK-STAT pathway activation were evaluated by PCR or western blot, along with correlation analyses between the evaluated markers and clinical parameters.
LSG from pSS patients showed increased p62 and decreased ATG5 expression, correlating negatively with increased activation of JAK-STAT pathway components (pSTAT1 and pSTAT3). Increased expression of STAT1 and IL-6 correlated with EULAR Sjögren's syndrome disease activity index and the presence of anti-Ro antibodies. ATG5-deficient 3D-acini reproduced the findings observed in LSG from pSS patients, showing increased expression of pro-inflammatory markers such as IL-6, which was reversed by tofacitinib.
Decreased expression of ATG5 in LSG epithelial cells from pSS patients possibly contributes to increased inflammation associated with JAK-STAT pathway activation, as evidenced in ATG5-deficient 3D-acini. Interestingly, these results suggest that tofacitinib could be used as an anti-inflammatory agent in pSS patients.
干燥综合征（SS）患者唾液腺（SG）上皮细胞的稳态失衡可能是导致炎症、分泌功能障碍和自身免疫的起始因素。自噬是一种重要的稳态机制，其缺陷与炎症和 Janus 激酶（JAK）-信号转导和转录激活因子（STAT）成分的积累有关。我们旨在评估原发性 SS（pSS）患者的唇 SG（LSG）上皮细胞中自噬是否发生改变，以及自噬是否通过 JAK-STAT 途径导致炎症。此外，我们研究了 JAK 抑制剂托法替尼在自噬缺陷（ATG5 敲低）三维（3D）腺中的抗炎作用。
我们分析了 12 名低焦点评分的 pSS 患者和 10 名对照的 LSG 活检。生成 ATG5 缺陷的 3D 腺，并在存在或不存在托法替尼的情况下用 IL-6 孵育。通过 PCR 或 Western blot 评估自噬标志物、促炎细胞因子表达和 JAK-STAT 途径激活，并对评估标志物与临床参数之间的相关性进行分析。
pSS 患者的 LSG 显示 p62 增加和 ATG5 表达减少，与 JAK-STAT 途径成分（pSTAT1 和 pSTAT3）的激活负相关。STAT1 和 IL-6 的表达增加与 EULAR 干燥综合征疾病活动指数和抗 Ro 抗体的存在相关。ATG5 缺陷的 3D 腺再现了 pSS 患者 LSG 中观察到的发现，显示出促炎标志物如 IL-6 的表达增加，托法替尼可逆转这一现象。
pSS 患者 LSG 上皮细胞中 ATG5 的表达减少可能导致 JAK-STAT 途径激活相关的炎症增加，正如 ATG5 缺陷的 3D 腺中所证明的那样。有趣的是，这些结果表明托法替尼可作为 pSS 患者的抗炎药物。
