Autoimmunity, Transplantation & Inflammation, Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland.
Chemical Biology & Therapeutics, Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland.
Biochem Biophys Res Commun. 2021 Mar 19;545:177-182. doi: 10.1016/j.bbrc.2021.01.051. Epub 2021 Feb 6.
The NLRP3 inflammasome is a critical component of the innate immune response to sterile inflammation. Its regulation involves a priming step, required for up-regulation of inflammasome protagonists and an activation step leading to NLRP3 inflammasome complex assembly, which triggers caspase-1 activity. The IκKβ kinase regulates canonical NF-κB, a key pathway involved in transcriptional priming. We found that IκKβ also regulates the activation and function of the NLRP3 inflammasome beyond the priming step. Two unrelated IκKβ inhibitors, AFN700 and TPCA-1, when applied after priming, fully blocked IL-1β secretion triggered by nigericin in THP-1 cells. Both inhibitors prevented neither inflammasome assembly, as monitored by measuring the formation of ASC specks, nor the generation of caspase-1 p20, a hallmark of caspase-1 activity, but they impaired the initial cleavage and activation of procaspase-1. These data thus indicate that IκKβ activity is required for efficient activation of NLRP3, suggesting that IκKβ may fulfill a dual role in coupling priming and activation of the NLRP3 inflammasome.
NLRP3 炎性小体是对非感染性炎症的先天免疫反应的关键组成部分。其调节涉及引发步骤，该步骤需要上调炎性小体的主角，以及激活步骤，导致 NLRP3 炎性小体复合物组装，从而触发半胱天冬酶-1 活性。IκKβ 激酶调节经典 NF-κB，这是参与转录引发的关键途径。我们发现，IκKβ 激酶除了引发步骤之外，还调节 NLRP3 炎性小体的激活和功能。两种不相关的 IκKβ 抑制剂，AFN700 和 TPCA-1，在引发后应用时，完全阻断了 Nigericin 在 THP-1 细胞中触发的 IL-1β 分泌。这两种抑制剂既没有阻止 ASC 斑点的形成，也没有阻止半胱天冬酶-1 的生成，作为半胱天冬酶-1 活性的标志，p20，但它们损害了前半胱天冬酶-1 的初始切割和激活。因此，这些数据表明 IκKβ 活性是 NLRP3 有效激活所必需的，这表明 IκKβ 可能在连接 NLRP3 炎性小体的引发和激活中发挥双重作用。
