P2Y6 Receptor Activation Aggravates NLRP3-dependent Microglial Pyroptosis via Downregulation of the PI3K/AKT Pathway in a Mouse Model of Intracerebral Hemorrhage

Pro-inflammatory signals generated after intracerebral hemorrhage (ICH) trigger a form of regulated cell death known as pyroptosis in microglia. White matter injury (WMI) refers to the condition where the white matter area of the brain suffers from mechanical, ischemic, metabolic, or inflammatory da...

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Vydané v:	Molecular neurobiology Ročník 61; číslo 7; s. 4259 - 4277
Hlavní autori:	Li, Yulong, Tu, Huiru, Zhang, Shengfan, Ding, Zhiquan, Wu, Guiwei, Piao, Jifeng, Lv, Dingyi, Hu, Libin, Li, Feng, Wang, Qinghua
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	New York Springer US 01.07.2024 Springer Nature B.V
Predmet:	1-Phosphatidylinositol 3-kinase AKT protein Animals Biomedical and Life Sciences Biomedicine Brain injury Caspase-1 Cell Biology Cell death Central nervous system Central nervous system diseases Cerebral Hemorrhage - complications Cerebral Hemorrhage - metabolism Cerebral Hemorrhage - pathology Collagenase Disease Models, Animal Down-regulation Down-Regulation - drug effects Edema Hematoma Hemorrhage Immunofluorescence Ischemia Kinases Male Mice Mice, Inbred C57BL Microglia Microglia - drug effects Microglia - metabolism Microglia - pathology Neurobiology Neurological diseases Neurology Neurosciences NLR Family, Pyrin Domain-Containing 3 Protein - metabolism Phosphatidylinositol 3-Kinases - metabolism Proto-Oncogene Proteins c-akt - metabolism Pyroptosis Pyroptosis - drug effects Receptor mechanisms Receptors, Purinergic P2 - metabolism Signal Transduction - drug effects Stroke Substantia alba Intracerebral Hemorrhage Microglial Pyroptosis Neuroinflammation P2Y6R White Matter Injury PI3K/AKT Pathway
ISSN:	0893-7648, 1559-1182, 1559-1182
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Shrnutí:	Pro-inflammatory signals generated after intracerebral hemorrhage (ICH) trigger a form of regulated cell death known as pyroptosis in microglia. White matter injury (WMI) refers to the condition where the white matter area of the brain suffers from mechanical, ischemic, metabolic, or inflammatory damage. Although the p2Y purinoceptor 6 (P2Y6R) plays a significant role in the control of inflammatory reactions in central nervous system diseases, its roles in the development of microglial pyroptosis and WMI following ICH remain unclear. In this study, we sought to clarify the role of P2Y6R in microglial pyroptosis and WMI by using an experimental mouse model of ICH. Type IV collagenase was injected into male C57BL/6 mice to induce ICH. Mice were then treated with MRS2578 and LY294002 to inhibit P2Y6R and phosphatidylinositol 3-kinase (PI3K), respectively. Bio-conductivity analysis was performed to examine PI3K/AKT pathway involvement in microglial pyroptosis. Quantitative Real-Time PCR, immunofluorescence staining, and western blot were conducted to examine microglial pyroptosis and WMI following ICH. A modified Garcia test, corner turning test, and forelimb placement test were used to assess neurobehavior. Hematoxylin-eosin staining (HE) was performed to detect cells damage around hematoma. Increases in the expression of P2Y6R, NLRP3, ASC, Caspase-1, and GSDMD were observed after ICH. P2Y6R was only expressed on microglia. MRS2578, a specific inhibitor of P2Y6R, attenuated short-term neurobehavioral deficits, brain edema and hematoma volume while improving both microglial pyroptosis and WMI. These changes were accompanied by decreases in pyroptosis-related proteins and pro-inflammatory cytokines both in vivo and vitro. Bioinformatic analysis revealed an association between the PI3K/AKT pathway and P2Y6R-mediated microglial pyroptosis. The effects of MRS2578 were partially reversed by treatment with LY294002, a specific PI3K inhibitor. P2Y6R inhibition alleviates microglial pyroptosis and WMI and ameliorates neurological deficits through the PI3K/AKT pathway after ICH. Consequently, targeting P2Y6R might be a promising approach for ICH treatment.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0893-7648 1559-1182 1559-1182
DOI:	10.1007/s12035-023-03834-6