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.
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