Aryl hydrocarbon receptor modulates stroke-induced astrogliosis and neurogenesis in the adult mouse brain.

Autor: Chen WC; Department and Institute of Physiology, National Yang-Ming University, No.155, Sec. 2, Linong Street, Beitou District, Taipei, 11217, Taiwan., Chang LH; Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan., Huang SS; Department of Pharmacology, Institute of Medicine, Chung-Shan Medical University, Taichung, Taiwan., Huang YJ; Department and Institute of Physiology, National Yang-Ming University, No.155, Sec. 2, Linong Street, Beitou District, Taipei, 11217, Taiwan., Chih CL; Cheng Hsin General Hospital, Taipei, Taiwan., Kuo HC; Stem Cell Program, Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan., Lee YH; Department and Institute of Physiology, National Yang-Ming University, No.155, Sec. 2, Linong Street, Beitou District, Taipei, 11217, Taiwan. yhlee3@ym.edu.tw.; Brain Research Center, National Yang-Ming University, Taipei, Taiwan. yhlee3@ym.edu.tw., Lee IH; Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan. ihlee@vghtpe.gov.tw.; Brain Research Center, National Yang-Ming University, Taipei, Taiwan. ihlee@vghtpe.gov.tw.; Division of Cerebrovascular Diseases, Neurological Institute, Taipei Veterans General Hospital, No.201, Sec. 2, Shipai Rd., Beitou District, Taipei, 11217, Taiwan. ihlee@vghtpe.gov.tw.
Jazyk: angličtina
Zdroj: Journal of neuroinflammation [J Neuroinflammation] 2019 Oct 12; Vol. 16 (1), pp. 187. Date of Electronic Publication: 2019 Oct 12.
DOI: 10.1186/s12974-019-1572-7
Abstrakt: Background: The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor activated by environmental agonists and dietary tryptophan metabolites for the immune response and cell cycle regulation. Emerging evidence suggests that AHR activation after acute stroke may play a role in brain ischemic injury. However, whether AHR activation alters poststroke astrogliosis and neurogenesis remains unknown.
Methods: We adopted conditional knockout of AHR from nestin-expressing neural stem/progenitor cells (AHRcKO) and wild-type (WT) mice in the permanent middle cerebral artery occlusion (MCAO) model. WT mice were treated with either vehicle or the AHR antagonist 6,2',4'-trimethoxyflavone (TMF, 5 mg/kg/day) intraperitoneally. The animals were examined at 2 and 7 days after MCAO.
Results: The AHR signaling pathway was significantly upregulated after stroke. Both TMF-treated WT and AHRcKO mice showed significantly decreased infarct volume, improved sensorimotor, and nonspatial working memory functions compared with their respective controls. AHR immunoreactivities were increased predominantly in activated microglia and astrocytes after MCAO compared with the normal WT controls. The TMF-treated WT and AHRcKO mice demonstrated significant amelioration of astrogliosis and microgliosis. Interestingly, these mice also showed augmentation of neural progenitor cell proliferation at the ipsilesional neurogenic subventricular zone (SVZ) and the hippocampal subgranular zone. At the peri-infarct cortex, the ipsilesional SVZ/striatum, and the hippocampus, both the TMF-treated and AHRcKO mice demonstrated downregulated IL-1β, IL-6, IFN-γ, CXCL1, and S100β, and concomitantly upregulated Neurogenin 2 and Neurogenin 1.
Conclusion: Neural cell-specific AHR activation following acute ischemic stroke increased astrogliosis and suppressed neurogenesis in adult mice. AHR inhibition in acute stroke may potentially benefit functional outcomes likely through reducing proinflammatory gliosis and preserving neurogenesis.
Databáze: MEDLINE
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