Abstract
BackgroundThe 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.MethodsWe 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.ResultsThe 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.ConclusionNeural 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.
Highlights
The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, is widely expressed in most mammalian tissues and evolutionarily conserved from invertebrates onward [1]
In the novel object recognition test for nonspatial working memory, we found that the TMF-treated mice and AHR conditional knockout (AHRcKO) mice explored the novel object more than the familiar object at 48 h and 7 days after middle cerebral artery occlusion (MCAO) (Fig. 1c)
Using the glioma C6-dioxin response elements (DRE)-luciferase cellbased assay of AHR agonist activities (Fig. 2c), in which AHR activation can be quantified by DRE-induced luciferase expression, the AHR agonist 6-formylindolo(3,2b)carbazole (FICZ) significantly increased AHR activity compared with the control
Summary
The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, is widely expressed in most mammalian tissues and evolutionarily conserved from invertebrates onward [1]. AHR is activated by a variety of ligands, including environmental pollutants such as. Environmental pollutants of AHR ligands cause developmental deficits of the brain and increased neuropsychiatric diseases [9,10,11]. AHR has been suggested to mediate acute ischemic injury following middle cerebral artery occlusion (MCAO) in adult mice. The AHR-dependent mechanisms underlying brain injury after acute stroke remains elusive. 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. Whether AHR activation alters poststroke astrogliosis and neurogenesis remains unknown
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