Wei Yankai, Sun Mei, Zhang Xinyu, Zhang Chengyuan, Yang Chao, Nian Hong, Du Bei, Wei Ruihua
Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, China.
Invest Ophthalmol Vis Sci. 2025 Jan 2;66(1):35. doi: 10.1167/iovs.66.1.35.
To investigate the role of S100A8/A9 in the pathogenesis of Sjögren's dry eye disease (SjDED) and explore its potential mechanism of action.
S100A8/A9 expression was determined by western blot and quantitative real-time polymerase chain reaction (qRT-PCR). Tear secretion, corneal fluorescein staining, and hematoxylin and eosin staining were used to evaluate the effect of paquinimod, a S100A8/A9 inhibitor, on dry eye disease in nonobese diabetic (NOD) mice. Immune cell infiltration and percentage were assessed by immunofluorescence and flow cytometry. Proinflammatory cytokine levels were examined by qRT-PCR or ELISA. The mechanism of action was analyzed using western blot, immunofluorescence, and chromatin immunoprecipitation.
S100A8/A9 was upregulated in peripheral blood mononuclear cells of patients with SjDED and lacrimal glands (LGs) of SjDED mice. The upregulation of S100A8/A9 was correlated with the dry eye severity and inflammatory infiltration levels in LGs. Administration of paquinimod ameliorated clinical and histopathological phenotypes of SjDED mice and reduced the proportion of Th17 cells in LGs, lymph nodes, and spleens. Further experiments revealed that S100A8/A9 did not directly affect Th17 generation and function but upregulated the expression of major histocompatibility complex Ⅱ (MHC Ⅱ) and Th17-polarizing cytokines in dendritic cells (DCs) to augment Th17 cell response. Mechanistically, S100A8/A9 induced the expression of Acod1 and thereby promoted the activation and nuclear translocation of signal transducer and activator of transcription 3 (STAT3), resulting in increased Il23a transcription. STAT3 activator reversed the therapeutic effect of paquinimod on SjDED mice.
S100A8/A9 activated the Acod1/STAT3 pathway to promote DC-driven Th17 cell responses in SjDED. The S100A8/A9/Acod1/STAT3 pathway may represent a promising therapeutic target for SjDED.
探讨S100A8/A9在干燥综合征干眼疾病（SjDED）发病机制中的作用，并探索其潜在作用机制。
采用蛋白质免疫印迹法和定量实时聚合酶链反应（qRT-PCR）检测S100A8/A9的表达。使用泪液分泌、角膜荧光素染色以及苏木精-伊红染色来评估S100A8/A9抑制剂帕喹莫德对非肥胖糖尿病（NOD）小鼠干眼疾病的影响。通过免疫荧光和流式细胞术评估免疫细胞浸润情况及比例。采用qRT-PCR或酶联免疫吸附测定（ELISA）检测促炎细胞因子水平。利用蛋白质免疫印迹法、免疫荧光和染色质免疫沉淀分析作用机制。
S100A8/A9在SjDED患者的外周血单个核细胞以及SjDED小鼠的泪腺（LG）中上调。S100A8/A9的上调与干眼严重程度以及LG中的炎症浸润水平相关。给予帕喹莫德可改善SjDED小鼠的临床和组织病理学表型，并降低LG、淋巴结和脾脏中Th17细胞的比例。进一步实验表明，S100A8/A9并不直接影响Th17的产生和功能，但上调树突状细胞（DC）中主要组织相容性复合体Ⅱ（MHCⅡ）和Th17极化细胞因子的表达，以增强Th17细胞反应。机制上，S100A8/A9诱导酰基辅酶A脱氢酶1（Acod1）的表达，从而促进信号转导子和转录激活子3（STAT3）的激活和核转位，导致白细胞介素23a（Il23a）转录增加。STAT3激活剂逆转了帕喹莫德对SjDED小鼠的治疗作用。
S100A8/A9激活Acod1/STAT3通路，以促进SjDED中DC驱动的Th17细胞反应。S100A8/A9/Acod1/STAT3通路可能是SjDED一个有前景的治疗靶点。
