TLR7/NLRP1固有免疫活化与自噬缺失在白癜风发病中的作用机制研究

Innate immune activation induces inflammation, meanwhile it can induce autophagy to promote inflammation subsidence and maintain cell homeostasis. Autophagy deficiency leads to the inactivation of proinflammatory regression, therefore the constant activation of innate immunity can lead to the continuation of inflammation and activation of the adaptive immunity leading to cell damage. Vitiligo is a depigmentation skin disease characterized by the targeted destruction of melanocytes. Our previous studies have shown there is innate immune abnormalities in the epidermis of patients with vitiligo and the autophagy of melanocyte is defective. However, how the interaction between innate immune activation and autophagy deficiency lead to pyroptosis of melanocytes has not been elucidated. In this study, we intend to investigate the effects of TLR7/NLRP1 innate immune activation and Atg7 autophagy deficiency on the pyroptosis of melanocytes by in vitro culture of melanocytes and animal models of vitiligo. Try to clarify the pathogenesis of vitiligo from the aspect of “homeostasis of innate immunity and autophagy ”. It is expected to maintain the stability of melanocytes by “inhibiting the activation of innate immunity ” and “promoting the activation of autophagy", so as to provide basis for exploring new method for treatment of vitiligo.

固有免疫活化诱导炎症反应的同时，可以诱导自噬促进炎症消退维持细胞稳态。如果细胞存在自噬缺陷，促炎症消退机制失活，不断活化的固有免疫则会导致炎症持续进行，激活适应性免疫应答导致细胞损伤。白癜风是一种以黑素细胞靶向性破坏为表现的色素脱失性皮肤病。我们既往研究显示：白癜风患者表皮存在固有免疫异常活化，黑素细胞自噬功能存在缺陷。但是固有免疫活化与自噬缺失如何相互作用导致黑素细胞焦亡，目前机制尚未明确。本研究拟通过黑素细胞体外培养和白癜风动物实验，过表达或抑制黑素细胞固有免疫分子TLR7，探讨TLR7/NLRP1固有免疫活化与Atg7自噬缺失对黑素细胞焦亡的影响，从“固有免疫与自噬稳态”角度阐述白癜风的发病机制。预期在治疗上采用“抑制固有免疫活化”兼顾“促进自噬活化”，从而维持黑素细胞稳态，为探索新的白癜风治疗方法提供依据。

白癜风的发病机制尚未完全阐明，既往研究发现细胞可通过自噬发挥自我调节作用，通过激活自噬反馈机制可以抑制固有免疫活化诱发的炎症反应。本项目旨在明确白癜风患者黑素细胞自噬功能存在缺失，不能拮抗固有免疫活化诱发的炎症反应，进而导致黑素细胞死亡引发白癜风。首先，通过本研究证实了黑素细胞TLR7在白癜风中存在异常表达，进一步可诱导下游炎性小体NLRP3活化及一系列炎症因子IL-1β，IL-18的表达增加，在白癜风发病中发挥作用。其次，通过本研究首次证实黑素细胞自噬信号活化与溶酶体TRPML1通道相关，通过激活TRPML1通道可以对黑素细胞氧化应激发挥保护作用；白癜风患者黑素细胞TRPML1通道表达和功能存在异常，对氧化应激的反馈调节作用下降，从而导致细胞容易发生氧化应激损伤。进一步，通过观察白癜风患者及小鼠模型炎性小体NLRP3表达变化，证实抑制炎性小体NLRP3活化可以发挥对白癜风的抵抗作用；通过采用脂质体靶向特异性敲除黑素细胞NLRP3，进一步证实NLRP3可以作为抑制白癜风发生发展的作用靶点。最后，通过探讨炎性小体NLRP3与自噬相关蛋白之间的相关性，提出白癜风的治疗应从抑制固有免疫活化与激活自噬两方面考虑，共同促进黑素细胞微环境的稳态平衡，抑制白癜风的发生发展，为白癜风的治疗提供了新的思路。