Enhanced autophagy alleviated corneal allograft rejection via inhibiting NLRP3 inflammasome activity
Enhanced autophagy alleviated corneal allograft rejection via inhibiting NLRP3 inflammasome activity
复制标题
增强自噬通过抑制 NLRP3 炎性体活性减轻角膜同种异体移植排斥
DOI：
10.1111/ajt.16968
复制
发表时间：
2022-02-15
影响因子：
8.8
通讯作者：
Gao, Hua
中科院分区：
文献类型：
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作者：
Wei, Chao;Ma, Li;Gao, Hua
自噬已被报道参与先天性和适应性免疫的许多方面。操纵自噬被认为是治疗免疫性疾病（包括同种异体移植物排斥和移植物抗宿主病）的有前途的治疗方法。然而，自噬是否与角膜移植排斥反应的发病机制密切相关仍不清楚。在这里，我们发现雷帕霉素（RAPA）诱导的自噬减轻角膜移植排斥反应。相反，用3-甲基腺嘌呤（3-MA）阻断自噬活性加重了角膜移植排斥反应。从机制上讲，我们揭示了RAPA增强的自噬周转通过NLRP 3降解抑制NLRP 3炎性小体活性。当通过巴弗洛霉素A1（BafA 1）阻断自噬体与溶酶体的融合时，由RAPA诱导的降低的NLRP 3炎性体活性显著恢复，NLRP 3和切割的Casp-1（p10）的蛋白水平以及IL-1 β分泌增加。此外，我们进一步揭示了阻断NLRP 3炎性体信号传导延长了角膜移植物的存活。总之，这些发现强调了增强的自噬在治疗角膜移植排斥反应中的关键作用，这为控制角膜移植排斥反应提供了另一种干预策略。
Autophagy has been reported to be involved in many aspects of innate and adaptive immunity. Manipulating autophagy is recognized as a promising therapeutic approach for treating immunological diseases, including allograft rejection, and graft-versus-host disease. However, whether autophagy was closely associated with the pathogenesis of corneal allograft rejection remains largely unknown. Here, we showed that rapamycin (RAPA)-induced autophagy alleviated corneal allograft rejection. By contrast, blocking autophagic activity using 3-methyladeine (3-MA) aggravated corneal transplantation rejection. Mechanistically, we revealed that the enhanced autophagic turnover by RAPA inhibited NLRP3 inflammasome activity through NLRP3 degradation. While blocking the fusion of autophagosomes with lysosomes by bafilomycin A1(BafA1), the reduced NLRP3 inflammasome activity induced by RAPA was significantly restored, with increased protein levels of NLRP3 and cleaved Casp-1(p10), as well as IL-1 beta secretion. Moreover, we further revealed that pharmacologically blocking NLRP3 inflammasome signaling prolonged the survival of corneal allografts. Taken together, these findings underscored the critical roles of enhanced autophagy in treating corneal allograft rejection, which provided an alternative intervention strategy to control corneal transplantation rejection.