| RRC ID |
58073
|
| 著者 |
Suzuki T, Kohyama K, Moriyama K, Ozaki M, Hasegawa S, Ueno T, Saitoe M, Morio T, Hayashi M, Sakuma H.
|
| タイトル |
Extracellular ADP augments microglial inflammasome and NF-κB activation via the P2Y12 receptor.
|
| ジャーナル |
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.
|
| 巻・号 |
50(2)
|
| ページ |
205-219
|
| 公開日 |
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
|
| 引用数 |
1
|
| リソース情報 |
| ヒト・動物細胞 |
MG6(RCB2403) |
