从PD-1/PD-L1信号通路调控M1/M2巨噬细胞极化探讨角膜化学伤的损伤修复机制与治疗

Ocular chemical burn is a common ophthalmic emergency disease which often leads to blindness in China. There is no effective treatment in this disease because of the unclear wound repair mechanism. Macrophage (Mф), as an important immune cell, is the most essential participating cell in tissue wound repair. Our previous studies found that Mф was the main inflammatory cell in mice corneal alkali burn model, and there were two subtypes of Mф, called classical activation Mф (M1) and selective activation Mф (M2). Furthermore, we found that M1 promoted inflammation and delayed corneal wound healing; M2 played a role in inhibiting inflammation and promoted corneal wound healing. Mф is the main target cell for the regulation of PD-1/PD-L1 pathway. Our previous studies found that up-regulation of PD-1 expression could promote corneal wound healing in corneal chemical burn. Furthermore, our results showed that up-regulation of PD-1 expression promoted Mф polarize to M2 in vitro. Previous studies showed that PD-1 could inhibit immune inflammation by up-regulation of IRF4. Moreover, IRF4/STAT6 could promote M2 polarization. Therefore, we propose the hypothesis that up-regulation of PD-1/PD-L1/IRF4/STAT6 signaling pathway can promote the repair of corneal chemical burn via regulating the Mф polarization to M2. We hopefully this research can provide new therapeutic targets and strategies for corneal chemical burn.

眼化学伤是我国常见的高致盲性眼科急症,其损伤修复机制不明,治疗棘手。巨噬细胞(Mф)是组织损伤修复中的关键细胞。我们的前期研究发现:在角膜化学伤模型中,Mф为主要炎症细胞,且存在经典激活Mф(M1)与选择激活Mф(M2)两种亚型,M1促进炎症反应、延缓角膜伤口愈合,M2抑制炎症、促进角膜伤口愈合。研究显示Mф是PD-1/PD-L1通路主要调控靶细胞。我们的前期研究发现:在角膜化学伤中上调PD-1促进角膜伤口愈合,且促进Mф极化为M2。PD-1可介导IRF4上调抑制炎症,而IRF4/STAT6促进M2极化。因此,我们提出:上调PD-1/PD-L1通路可介导IRF4/STAT6上调,继而诱导Mф极化为M2,可能抑制角膜化学伤的炎症损伤、促进伤口愈合。本课题拟通过探讨PD-1/PD-L1/IRF4/STAT6通路调控M1/M2极化在角膜化学伤中的作用机制,有望为角膜化学伤提供新的治疗靶点及策略。

项目背景：眼化学伤是我国常见的高致盲性眼科急症,其损伤修复机制不明,治疗棘手。巨噬细胞(Mф)是组织损伤修复中的关键细胞。我们的前期研究发现:在角膜化学伤模型中,Mф为主要炎症细胞,且存在经典激活Mф(M1)与选择激活Mф(M2)两种亚型,M1促进炎症反应、延缓角膜伤口愈合,M2抑制炎症、促进角膜伤口愈合。研究显示Mф是PD-1/PD-L1通路主要调控靶细胞。我们的前期研究发现:在角膜化学伤中上调PD-1促进角膜伤口愈合,且促进Mф极化为M2。PD-1可介导IRF4上调抑制炎症,而IRF4/STAT6促进M2极化。本课题拟通过探讨PD-1/PD-L1/IRF4/STAT6通路调控M1/M2极化在角膜化学伤中的作用机制,有望为角膜化学伤提供新的治疗靶点及策略。. 主要研究内容：（1）利用小鼠角膜碱烧伤模型，明确在角膜化学伤中PD-1 与PD-L1、IRF4、STAT6、Mф 浸润、M1/M2 亚型变化的关系及作用。（2）体外实验明确PD-1/PD-L1/IRF4/STAT6 通路调控M1/M2 极化的分子机制。（3）进一步体内实验验证PD-1/PD-L1/IRF4/STAT6 信号通路调控M1/M2 极化在角膜化学伤中的作用。. 重要结果：（1）发现在角膜化学伤中PD-1是起到促进角膜修复的作用（2）发现PD-1能促进巨噬细胞（Mф）向M2极化（3）发现在角膜化学伤中 PD-1/PD-L1是通过促进巨噬细胞（Mф）向M2极化起到促进角膜修复的作用（4）发现PD-1/PD-L1通路能促进Mф向M2极化，抑制Mф向M1极化（5）发现PD-1/PD-L1调控Mф向M2极化是通过IRF4、STAT6依赖的机制。. 科学意义：明确PD-1/PD-L1/IRF4/STAT6 调控M1/M2 巨噬细胞极化在角膜化学伤中的作用机制，进一步阐明角膜化学伤的损伤修复机理，有望为眼化学伤以及其他炎症损伤性疾病提供新的、潜在的治疗靶点。