自噬对NLRP3炎性体活化的调节在年龄相关性黄斑变性中的作用

Age-related macular degeneration (AMD) is the leading cause of irreversible central vision loss in the elderly. Multiple factors can cause retinal pigment epithelium (RPE) damage, which ultimately results in AMD. Up till now, the pathogenesis of AMD is not fully understood, thus, no methods have been discovered to effectively protect RPE during AMD. The NLPR3 inflammasome activation has been highlighted as a hot topic and an important pathway in AMD. Both proinflammatory IL-1β and IL-18 released by the activated NLRP3 inflammasome are the main cytokines that trigger AMD. By exogenous stimulation of human RPE mimicking AMD, we have found that not only the activated NLRP3 inflammasome is present in the stressed RPE, autophagy is obviously upregulated as well. More interestingly, a large amount of the NLRP3 inflammasome relocates to the autophagosome. Because autophagy is a cellular degradation process that maintains homeostasis, only low levels of basic autophagy occur during normal cellular activity. With the presence of such a highly upregulated autophagy process, we are wondering whether the upregulated autophagy occurring in the stressed RPE could suppress the activated NLRP3 inflammasome and protect RPE? Moreover, could the upregulated autophagy subsequently prevent or inhibit AMD via rescuing the damaged RPE? To elucidate these questions mentioned above, this study is aimed to evaluate the regulatory role of autophagy in the NLRP3 inflammasome activation and clarify the feedback loop between autophagy and the NLRP3 inflammasome activation. These innovative results would provide guidance on how to effectively protect RPE as well as prevent and inhibit AMD.

年龄相关性黄斑变性(AMD)是老年人群中不可逆性中央视力丧失的首要原因。多种因素累积可损伤黄斑区视网膜色素上皮(RPE)，导致AMD。由于AMD发病机制不明，至今尚无有效方法保护RPE并阻止AMD的发生或发展。新近研究表明，NLRP3炎性体活化是AMD发病机制的重要环节；其释放的IL-1β和IL-18，均是诱发AMD的重要因子。申请者发现，应激状态下，RPE除存在NLRP3炎性体活化外，还出现自噬显著上调；更为特别的是，NLRP3炎性体移位并大量聚集于自噬体内。自噬是维持细胞更新的手段，常态下仅少量出现。由此我们推测，RPE应激时自噬上调，是否能抑制NLRP3炎性体活化并保护RPE？此外，自噬上调是否可通过抑制RPE受损，阻止AMD的发生或发展？综上，本课题以自噬为起点，探索自噬对NLRP3炎性体活化的调节和二者可能存在的反馈机制，为保护RPE及阻止AMD的发生和发展提供全新的科学依据。

年龄相关性黄斑变性(AMD)是老年人群中不可逆性中央视力丧失的首要原因。课题组开展“自噬对NLRP3炎性体活化的调节在年龄相关性黄斑变性中的作用”，经过3年的探索，证明NLRP3炎性体通路重要因子的活化特异性损伤视网膜色素上皮(RPE)，是导致AMD的重要环节。此外，当体内存在持续慢性炎症后，RPE细胞内的NLRP3炎性体活化与自噬调节高度相关。实验结果表明，RPE应激时自噬上调，该过程能有效抑制NLRP3炎性体活化并保护RPE；应用NLRP3抑制剂可阻止AMD病变的发展。