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.
journal_name
Eur J Immunoljournal_title
European journal of immunologyauthors
Suzuki T,Kohyama K,Moriyama K,Ozaki M,Hasegawa S,Ueno T,Saitoe M,Morio T,Hayashi M,Sakuma Hdoi
10.1002/eji.201848013subject
Has Abstractpub_date
2020-02-01 00:00:00pages
205-219issue
2eissn
0014-2980issn
1521-4141journal_volume
50pub_type
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