Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, M13 9PT Manchester, United Kingdom.
Molecular Inflammation Group, University Clinical Hospital Virgen de la Arrixaca, Biomedical Research Institute of Murcia, 30120 Murcia, Spain.
Proc Natl Acad Sci U S A. 2018 Oct 2;115(40):E9371-E9380. doi: 10.1073/pnas.1812744115. Epub 2018 Sep 19.
The NLRP3 inflammasome is an important regulator of inflammation and immunity. It is a multimolecular platform formed within cells that facilitates the activation of proinflammatory caspases to drive secretion of cytokines such as interleukin-1β (IL-1β). Knowledge of the mechanisms regulating formation of the NLRP3 inflammasome is incomplete. Here we report Cl channel-dependent formation of dynamic ASC oligomers and inflammasome specks that remain inactive in the absence of K efflux. Formed after Cl efflux exclusively, ASC specks are NLRP3 dependent, reversible, and inactive, although they further prime inflammatory responses, accelerating and enhancing release of IL-1β in response to a K efflux-inducing stimulus. NEK7 is a specific K sensor and does not associate with NLRP3 under conditions stimulating exclusively Cl efflux, but does after K efflux, activating the complex driving inflammation. Our investigation delivers mechanistic understanding into inflammasome activation and the regulation of inflammatory responses.
NLRP3 炎性小体是炎症和免疫的重要调节剂。它是细胞内形成的多分子平台，有助于激活促炎半胱天冬酶，从而驱动细胞因子如白细胞介素-1β（IL-1β）的分泌。调控 NLRP3 炎性小体形成的机制尚不完全清楚。在这里，我们报告了 Cl 通道依赖性 ASC 寡聚体和炎性小体斑点的形成，在没有 K 外流的情况下，这些斑点仍然处于无活性状态。Cl 外流后形成的 ASC 斑点依赖于 NLRP3，是可逆的且无活性的，尽管它们进一步引发炎症反应，加速并增强对 K 外流诱导刺激物的 IL-1β 的释放。NEK7 是一种特定的 K 感受器，在仅刺激 Cl 外流的条件下不与 NLRP3 相关联，但在 K 外流后会与之关联，从而激活驱动炎症的复合物。我们的研究为炎性小体激活和炎症反应的调控提供了机制上的理解。
