Abstract
BackgroundNucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) plays an important role in mediating inflammatory responses during ischemic stroke. Bile acid receptor Takeda-G-protein-receptor-5 (TGR5) has been identified as an important component in regulating brain inflammatory responses. In this study, we investigated the mechanism of TGR5 in alleviating neuroinflammation after middle cerebral artery occlusion (MCAO).MethodsSprague-Dawley rats were subjected to MCAO and TGR5 agonist INT777 was administered intranasally 1 h after MCAO. Small interfering RNAs (siRNA) targeting TGR5 and Pellino3 were administered through intracerebroventricular injection 48 h before MCAO. Infarct volumes and neurologic scores were evaluated, and ELISA, flow cytometry, immunofluorescence staining, immunoblotting, and co-immunoprecipitation were used for the evaluations.ResultsEndogenous TGR5 and Pellino3 levels increased after MCAO. TGR5 activation by INT777 significantly decreased pro-inflammatory cytokine, cleaved caspase-8, and NLRP3 levels, thereby reducing brain infarctions; both short- and long-term neurobehavioral assessments showed improvements. Ischemic damage induced the interaction of TGR5 with Pellino3. Knockdown of either TGR5 or Pellino3 increased the accumulation of cleaved caspase-8 and NLRP3, aggravated cerebral impairments, and abolished the anti-inflammatory effects of INT777 after MCAO.ConclusionsTGR5 activation attenuated brain injury by inhibiting neuroinflammation after MCAO, which could be mediated by Pellino3 inhibition of caspase-8/NLRP3.
Highlights
Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) plays an important role in mediating inflammatory responses during ischemic stroke
Recent findings demonstrate that the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome, which is abundantly expressed in the brain, plays an important role in detecting cellular damage and mediating inflammatory responses to aseptic tissue injury during ischemic stroke [4,5,6]
Ten animals were excluded; the excluded rats included animals that did not show signs of neurobehavioral deficits when waking up from middle cerebral artery occlusion (MCAO) or animals in which subarachnoid hemorrhage was observed at necropsy
Summary
Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) plays an important role in mediating inflammatory responses during ischemic stroke. We investigated the mechanism of TGR5 in alleviating neuroinflammation after middle cerebral artery occlusion (MCAO). Recent findings demonstrate that the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome, which is abundantly expressed in the brain, plays an important role in detecting cellular damage and mediating inflammatory responses to aseptic tissue injury during ischemic stroke [4,5,6]. In central nervous system (CNS) research, studies have shown that TGR5 activation alleviates neuroinflammation and improves outcomes in models of experimental autoimmune encephalomyelitis and hepatic encephalopathy [11, 12]. Our previous research showed that TGR5 activation alleviates brain injury following middle cerebral artery occlusion (MCAO) [13]. The effects of TGR5 on neuroinflammation after ischemic stroke have not been investigated
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