TGR5 activation attenuates neuroinflammation via Pellino3 inhibition of caspase-8/NLRP3 after middle cerebral artery occlusion in rats

Abstract Background Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) plays an important role in mediating inflammatory responses during ischemic stroke. Bile acid Takeda-G-protein-receptor-5 (TGR5) has been identified as component regulating brain responses. In this study, we investigated the mechanism of TGR5 alleviating neuroinflammation after middle cerebral artery occlusion (MCAO). Methods Sprague-Dawley rats were subjected to MCAO and agonist INT777 was administered intranasally 1 h MCAO. Small interfering RNAs (siRNA) targeting Pellino3 through intracerebroventricular injection 48 before Infarct volumes neurologic scores evaluated, ELISA, flow cytometry, immunofluorescence staining, immunoblotting, co-immunoprecipitation used for evaluations. Results Endogenous levels increased activation by significantly decreased pro-inflammatory cytokine, cleaved caspase-8, NLRP3 levels, thereby reducing infarctions; both short- long-term neurobehavioral assessments showed improvements. Ischemic damage induced interaction with Pellino3. Knockdown either or accumulation caspase-8 NLRP3, aggravated impairments, abolished anti-inflammatory effects Conclusions attenuated injury inhibiting MCAO, which could be mediated inhibition caspase-8/NLRP3.