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

  • Liang, Hui1, 2
  • Matei, Nathanael2
  • McBride, Devin W.3
  • Xu, Yang2
  • Zhou, Zhenhua2
  • Tang, Jiping2
  • Luo, Benyan1
  • Zhang, John H.2
  • 1 Zhejiang University School of Medicine, Hangzhou, China , Hangzhou (China)
  • 2 Loma Linda University, 11041 Campus St, Risley Hall, Room 219, Loma Linda, CA, 92354, USA , Loma Linda (United States)
  • 3 The University of Texas Health Science Center at Houston, Houston, TX, USA , Houston (United States)
Published Article
Journal of Neuroinflammation
Springer (Biomed Central Ltd.)
Publication Date
Feb 02, 2021
DOI: 10.1186/s12974-021-02087-1
Springer Nature


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.

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