PDF(Pubmed)
Abstract：
NLRP3 is an important innate immune sensor that responses to various signals and forms the inflammasome complex, leading to IL-1β secretion and pyroptosis. Lysosomal damage has been implicated in NLRP3 inflammasome activation in response to crystals or particulates, but the mechanism remains unclear. We developed the small molecule library screening and found that apilimod, a lysosomal disruptor, is a selective and potent NLRP3 agonist. Apilimod promotes the NLRP3 inflammasome activation, IL-1β secretion, and pyroptosis. Mechanismically, while the activation of NLRP3 by apilimod is independent of potassium efflux and directly binding, apilimod triggers mitochondrial damage and lysosomal dysfunction. Furthermore, we found that apilimod induces TRPML1-dependent calcium flux in lysosomes, leading to mitochondrial damage and the NLRP3 inflammasome activation. Thus, our results revealed the pro-inflammasome activity of apilimod and the mechanism of calcium-dependent lysosome-mediated NLRP3 inflammasome activation.
摘要：
NLRP3是一种重要的先天性免疫传感器，可响应各种信号并形成炎症复合体，导致IL-1β分泌和焦亡。溶酶体损伤与响应晶体或颗粒的NLRP3炎性体激活有关，但机制尚不清楚。我们开发了小分子文库筛选，发现阿吡莫德，溶酶体干扰物,是选择性和有效的NLRP3激动剂。阿吡莫德促进NLRP3炎性体激活，IL-1β分泌，和焦亡。机械上,而阿吡莫德对NLRP3的激活独立于钾外排和直接结合，阿吡莫德引发线粒体损伤和溶酶体功能障碍。此外，我们发现阿吡莫德在溶酶体中诱导TRPML1依赖性钙通量，导致线粒体损伤和NLRP3炎性体激活。因此，我们的结果揭示了阿吡莫德的促炎性体活性和钙依赖性溶酶体介导的NLRP3炎性体激活的机制。
