Hari Aswin, Zhang Yifei, Tu Zhongyuan, Detampel Pascal, Stenner Melanie, Ganguly Anutosh, Shi Yan
Department of Microbiology, Immunology &Infectious Diseases and Snyder Institute, University of Calgary, Calgary, Alberta, Canada.
Department of Basic Medical Sciences, School of Medicine; Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, China.
Sci Rep. 2014 Dec 2;4:7281. doi: 10.1038/srep07281.
Crystalline structures activate the NLRP3 inflammasome, leading to the production of IL-1β, however, the molecular interactions responsible for NLRP3 activation are not fully understood. Cathepsin B release from the ruptured phagolysosome and potassium ion efflux have been suggested to be critical for this activation. Here, we report that Cathepsin B redistribution was not a crucial event in crystal-induced IL-1β production. Silica and monosodium urate crystal-treated macrophages with undisturbed lysosomes demonstrated strong co-localization of ASC and Caspase-1, indicative of NLRP3 inflammasome activation. Importantly, we provided evidence to suggest that macrophage cell membrane binding to immobilized crystals was sufficient to induce IL-1β release, and this activation of the NLRP3 inflammasome was inhibited by blocking potassium efflux. Therefore, this work reveals additional complexity in crystalline structure-mediated NLRP3 inflammasome regulations.
晶体结构激活NLRP3炎性小体，导致白细胞介素-1β（IL-1β）的产生，然而，负责NLRP3激活的分子相互作用尚未完全明确。已表明，来自破裂吞噬溶酶体的组织蛋白酶B释放和钾离子外流对此激活至关重要。在此，我们报告组织蛋白酶B的重新分布并非晶体诱导IL-1β产生的关键事件。溶酶体未受干扰的二氧化硅和尿酸钠晶体处理的巨噬细胞显示ASC和半胱天冬酶-1有强烈的共定位，表明NLRP3炎性小体被激活。重要的是，我们提供的证据表明巨噬细胞膜与固定化晶体的结合足以诱导IL-1β释放，并且通过阻断钾外流可抑制NLRP3炎性小体的这种激活。因此，这项研究揭示了晶体结构介导的NLRP3炎性小体调节中存在的更多复杂性。
