RRC ID 58073
Author Suzuki T, Kohyama K, Moriyama K, Ozaki M, Hasegawa S, Ueno T, Saitoe M, Morio T, Hayashi M, Sakuma H.
Title Extracellular ADP augments microglial inflammasome and NF-κB activation via the P2Y12 receptor.
Journal Eur J Immunol
Abstract The NLRP3 inflammasome is a molecular complex that translates signals from pathogens and tissue damage into inflammatory responses, and plays crucial roles in numerous neurological diseases. Activation of the NLRP3 inflammasome leads to caspase-1 dependent cleavage of pro-IL-1β to form mature IL-1β. By acting on the P2X7 purinergic receptor, extracellular ATP is one of the major stimuli that activates the NLRP3 inflammasome. Although microglia express multiple purinergic receptors, their roles in inflammasome-mediated inflammation are largely unknown. We studied the role of the P2Y12 receptor, a metabotropic P2Y receptor enriched in microglia, on inflammation in vitro. Inhibition of the microglial P2Y12 receptor by PSB0739 or siRNA knockdown suppressed IL-1β release. P2Y12 receptor-deficient microglia displayed markedly attenuated IL-1β mRNA expression and release. P2Y12 receptor blockade also suppressed IL-6 production. Both IL-1β and IL-6 responses were augmented by extracellular ADP or ADP-βS and were abrogated by PSB0739. Mechanistically, ADP-βS potentiated NF-κB activation. In addition, ADP altered mitochondrial membrane potential in combination with ATP and increased the number of caspase-1 positive cells through the P2Y12 receptor. These results elucidate a novel inflammatory mechanism by which extracellular ADP acts on the P2Y12 receptor to activate NF-κB and the NLRP3 inflammasome to enhance microglial inflammation.
Volume 50(2)
Pages 205-219
Published 2020-2-1
DOI 10.1002/eji.201848013
PMID 31549730
MeSH Adenosine Diphosphate / metabolism* Animals Caspase 1 / metabolism Cell Line Cytokines / metabolism Gene Expression Regulation / physiology Inflammasomes / metabolism* Inflammation / metabolism Inflammation Mediators / metabolism Interleukin-1beta / metabolism Macrophages / metabolism Mice NF-kappa B / metabolism* Reactive Oxygen Species / metabolism Receptors, Purinergic P2Y12 / metabolism* Signal Transduction / physiology
IF 4.404
Times Cited 1
Human and Animal Cells MG6(RCB2403)