Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
Glia. 2013 Jul;61(7):1113-21. doi: 10.1002/glia.22499. Epub 2013 Apr 26.
Central nervous system (CNS) trauma involves extensive cellular damage that is due, in part, to an innate inflammatory response induced by extracellular ATP. The innate immune response is regulated by pattern recognition receptors (PRRs), which include NOD-like receptors (NLRs). The PRRs and signaling cascades that regulate innate glial responses to CNS injury remain largely undefined. In this report, we show that human astrocytes express the NLR protein 2 (NLRP2) inflammasome that is activated by the danger associated molecular pattern (DAMP) ATP. The NLRP2 inflammasome is a multiprotein complex that consists of NLRP2, the adaptor protein apoptosis-speck-like protein containing a caspase recruitment domain (ASC) and caspase-1. NLRP2 also interacts with the P2X7 receptor and the pannexin 1 channel. Stimulation of human astrocytes with ATP resulted in activation of the NLRP2 inflammasome leading to the processing of inflammatory caspase-1 and interleukin-1β (IL-1β). ATP-induced activation of the NLRP2 inflammasome was inhibited by the pannexin 1 inhibitor probenecid and by the P2X7 receptor antagonist Brilliant Blue G (BBG). siRNA knockdown of NLRP2 significantly decreased NLRP2 levels and caspase-1 processing in human astrocytes in response to ATP. Our findings suggest that the astrocytic NLRP2 inflammasome is an important component of the CNS inflammatory response and that the NLRP2 inflammasome may be a therapeutic target to inhibit inflammation induced by CNS injury.
中枢神经系统（CNS）创伤涉及广泛的细胞损伤，部分原因是细胞外 ATP 诱导的固有炎症反应。先天免疫反应受模式识别受体（PRRs）调节，包括 NOD 样受体（NLRs）。调节先天神经胶质对 CNS 损伤反应的 PRRs 和信号级联反应在很大程度上尚未确定。在本报告中，我们表明人星形胶质细胞表达 NLR 蛋白 2（NLRP2）炎症小体，该炎症小体被危险相关分子模式（DAMP）ATP 激活。NLRP2 炎症小体是一种多蛋白复合物，由 NLRP2、包含半胱天冬酶募集结构域（ASC）的凋亡斑点样蛋白的衔接蛋白（ASC）和半胱天冬酶-1 组成。NLRP2 还与 P2X7 受体和 Pannexin 1 通道相互作用。用 ATP 刺激人星形胶质细胞可导致 NLRP2 炎症小体的激活，导致炎症性半胱天冬酶-1 和白细胞介素-1β（IL-1β）的加工。Pannexin 1 抑制剂 Probenecid 和 P2X7 受体拮抗剂 Brilliant Blue G（BBG）抑制了 ATP 诱导的 NLRP2 炎症小体的激活。NLRP2 的 siRNA 敲低显著降低了人星形胶质细胞中 NLRP2 的水平和对 ATP 的半胱天冬酶-1 加工。我们的研究结果表明，星形胶质细胞 NLRP2 炎症小体是 CNS 炎症反应的重要组成部分，并且 NLRP2 炎症小体可能是抑制 CNS 损伤引起的炎症的治疗靶点。
