辛伐他汀靶向RAGE-CXCL16阻断CD8+T细胞皮肤迁移在白癜风治疗中的作用及机制研究

Vitiligo is a common and refractory autoimmune skin disease, for which there is still no effective therapeutic agents so far. Under oxidative stress, keratinocytes can secret the chemokine CXCL16 and thus induce the skin trafficking of CD8+T cells that destroy melanocytes, which is a key event in the development of vitiligo. Therefore, targeting the process to inhibit the cutaneous infiltration of CD8+T cells could be a new strategy for the treatment of vitiligo. Our previous studies have demonstrated that simvastatin can inhibit the secretion of CXCL16 from keratinocytes under oxidative stress. Moreover, simvastatin could decrease the expression of RAGE, a pattern recognition receptior that contributes to the production and the secretion of multiple chemokines. Based on these findings, we hypothesize that simvastatin could inhibit the secretion of CXCL16 from keratinocytes via blocking the expression and the activation of RAGE under oxidative stress, which subsequently attenuates the skin trafficking of CD8+T cells and thus protects melanocytes against immune injury in vitiligo. To testify our hypothesis, this project will first verify whether simvastatin could block the skin trafficking of CD8+T cells by targeting RAGE-CXCL16 axis and investigate the underlying mechanism at cell level. Moreover, we will testify the results of the in vitro experiments in clinical specimens. The findings of this project can help to clarify the specific mechanism underlying the protection of simvastatin on melanocytes against immune injury and to explore a safe and effective medicine for the treatment of vitiligo.

白癜风是一种常见的难治性自身免疫性皮肤病，临床尚缺乏有效治疗药物。氧化应激下角质形成细胞释放趋化因子CXCL16，介导CD8+T细胞皮肤迁移并杀伤黑素细胞，是白癜风发病的关键环节，靶向此过程阻断CD8+T细胞皮肤迁移是白癜风治疗的新策略。我们前期研究发现辛伐他汀抑制氧化应激下角质形成细胞分泌CXCL16，同时观察到其亦可降低模式识别受体RAGE的表达，后者已被证实参与多种趋化因子的生成与释放。据此我们提出研究假说：辛伐他汀通过抑制氧化应激下角质形成细胞RAGE的表达和活化，降低CXCL16分泌，阻断CD8+T细胞皮肤迁移，保护黑素细胞抵抗免疫损伤，从而发挥治疗白癜风的作用。本项目拟在细胞水平探究辛伐他汀靶向RAGE-CXCL16阻断CD8+T细胞皮肤迁移的作用和机理，并在临床样本中进行验证，预期结果将阐明辛伐他汀保护黑素细胞抵抗免疫损伤的具体机制，为白癜风治疗探索安全有效的药物。

白癜风是一种由特异杀伤性CD8 T细胞介导黑素细胞损伤导致色素脱失的慢性自身免疫性皮肤病。角质形成细胞和CD8 T间形成的正反馈趋化信号环路是白癜风发生发展的关键环节，目前尚无针对这一复杂发病机制的治疗。T-96是雷公藤中提取的一种单体，具有抗炎，抑制免疫作用。本研究旨在探索T-96在白癜风治疗中的药理作用。我们发现一方面T-96可通过抑制CD8 T细胞的增殖活化及效应功能，抑制CD8 T细胞JAK3-STAT5通路，降低CD8 T细胞膜表面CXCR6和CXCR3的表达发挥免疫抑制作用，另一方面T-96可通过靶向氧化应激角质形成细胞中NF-κΒ p65抑制CXCL16的表达，靶向JAK2-STAT1信号抑制CXCL9和CXCL10的表达，进而阻断CD8 T细胞的趋化作用。体内研究发现T-96可改善白癜风动物模型黑素细胞的减少。我们的研究明确了T-96在白癜风中的潜在治疗作用和多靶点分子机制，为今后白癜风的临床治疗提供了新的思路。