S100A8/A9 promotes dendritic cell-mediated Th17 cell response in SS dry eye

Sjogren's syndrome (SS) dry eye is a chronic autoimmune eyedisease driven by T helper 17 (Th17)cells. S100A8/A9 has emerged as an important proinflammatory alarmin in variousautoimmune and inflammatory diseases. However, the role of S100A8/A9 in the pathogenesis of SS dry eye remains unexplored. Here,we show that the expression levels of S100A8/A9 were elevated in peripheral blood mononuclear cells (PBMCs) of patients with SS dry eye, as well as the lacrimal glands (LGs) of SS dry eye mice. The administration of paquinimod, a specific inhibitor of S100A8/A9, could alleviate the progression of SS dry eye with significant reduction of Th17 cell frequency in LGs, spleen and lymph nodes of SS dry eye mice.Further experiment revealed that S100A8/A9 did not directly affect Th17 generation and function, but upregulated the expression of MHCIl andI123a in DCs to augment Th17 cell response through a Acod1/STAT3-dependent signaling pathway in the context of SS dry eye. Together,these findings unveiled the key role of S100A8/A9 in the pathogenesis of SS dry eye and suggested a potential therapeutic avenue for SS dry eyeand otherTh7 cell-related autoimmune disorders. Overall design: We isolated bone marrow cells from SS dry eye mice to induce DCs, and stimulated DCs with recombinant S100A8/A9 or Vehicle. Total RNAs of Vehicle- or S100A8/A9-treated DCs were extracted using TRIzol® Reagent (Invitrogen). Then RNA-sequencing was performed to predict downstream signaling pathways involved in the regulatory effect of S100A8/A9 on DCs.

干燥综合征（Sjogren's syndrome, SS）相关性干眼是一种由辅助性T细胞17（T helper 17, Th17）细胞驱动的慢性自身免疫性眼病。S100A8/A9作为一类重要的促炎性警报素，已在多种自身免疫与炎症性疾病中被证实发挥关键调控作用，但目前其在干燥综合征相关性干眼发病机制中的功能仍未被阐明。
本研究发现，干燥综合征相关性干眼患者的外周血单个核细胞（peripheral blood mononuclear cells, PBMCs）以及干燥综合征相关性干眼模型小鼠的泪腺（lacrimal glands, LGs）中，S100A8/A9的表达水平均显著升高。给予S100A8/A9特异性抑制剂帕喹莫德（paquinimod）干预，可有效延缓干燥综合征相关性干眼的疾病进展，并显著降低模型小鼠泪腺、脾脏及淋巴结内Th17细胞的占比。
后续机制研究显示，在干燥综合征相关性干眼的病理微环境中，S100A8/A9并不会直接调控Th17细胞的生成与功能，而是通过Acod1/STAT3依赖的信号通路，上调树突状细胞（DCs）表面主要组织相容性复合体II类（MHCII）与白细胞介素23a（Il23a）的表达，从而增强Th17细胞的免疫应答。
综上，本研究揭示了S100A8/A9在干燥综合征相关性干眼发病过程中的核心调控作用，为干燥综合征相关性干眼及其他Th17细胞相关自身免疫性疾病提供了潜在的治疗靶点与干预策略。
实验整体设计：我们从干燥综合征相关性干眼模型小鼠体内分离骨髓细胞以诱导生成树突状细胞，随后分别用重组S100A8/A9或载体（Vehicle）刺激树突状细胞。采用TRIzol®试剂（Invitrogen）提取载体处理组与S100A8/A9处理组树突状细胞的总RNA，通过RNA测序（RNA-sequencing）预测S100A8/A9调控树突状细胞功能所涉及的下游信号通路。