糖皮质激素诱导的肿瘤坏死因子受体GITR是重要的共刺激分子，然而其在天然免疫和炎症中的功能仍不清楚。预实验结果显示，细菌感染小鼠角膜后GITR表达上调，而敲除GITR可以抑制角膜浸润的巨噬细胞死亡，减轻角膜溃疡，提示GITR可能通过促进巨噬细胞死亡介导角膜炎症损伤。进一步体外实验发现，GITR特异性抑制细菌第二信使c-di-GMP诱导的炎症小体活化和巨噬细胞焦亡。通过免疫共沉淀和质谱分析，我们发现胞内DNA受体IFIX可与GITR结合，并证实IFIX可识别c-di-GMP，介导巨噬细胞焦亡。我们先前报道，巨噬细胞焦亡是介导角膜溃疡的关键因素。结合文献报道和预实验结果，我们提出“GITR通过胞内DNA受体IFIX上调c-di-GMP诱导的巨噬细胞焦亡，介导角膜炎症损伤”的假说，并拟通过体内外模型，揭示GITR和IFIX调控巨噬细胞焦亡的分子机制，为角膜炎防治提供新的靶点和理论依据。

Glucocorticoid-induced tumor necrosis factor receptor (GITR) is an important co-stimulatory molecule on lymphocytes, however, its role on innate immunity and inflammatory response remains unclear. Our preliminary data showed that bacterial infection up-regulated GITR expression in infected mouse corneas, while knockout of GITR reduced the death of corneal infiltrated macrophages and suppressed corneal ulceration, indicating that GITR may induce corneal inflammatory damage by promoting macrophage death. Furthermore, our in vitro experiments demonstrated that GITR specifically inhibited inflammasome activation and macrophage pyroptosis induced by bacterial second messenger, c-di-GMP. Using immune co-precipitation assay and mass spectrum analysis, we identified that intracellular DNA sensor IFIX can interact with GITR, and recognize c-di-GMP to induce macrophage pyroptosis. Previously, our group has reported that macrophage pyroptosis is the key factor resulting in corneal ulceration. Based on the literature and preliminary results, we proposed a hypothesis that GITR promotes the c-di-GMP-induced macrophage pyroptosis through intracellular DNA sensor IFIX, and therefore leads to corneal inflammatory damage. We will use both in vivo and in vitro model, to explore the underlying mechanism of GITR and IFIX in modulating macrophage pyroptosis and corneal inflammation. This project may provide new targets and theoretical supports to the prevention and treatment of bacterial keratitis.