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The aryl hydrocarbon receptor ( AhR ) is a heterodimeric transcriptional regulator with pleiotropic functions in xenobiotic metabolism and detoxification, vascular development and cancer. Herein, we report a previously undescribed role for the  AhR  signalling pathway in the pathogenesis of the wet, neovascular subtype of age‐related macular degeneration ( AMD ), the leading cause of vision loss in the elderly in the Western world. Comparative analysis of gene expression profiles of aged   AhR  −/−   and wild‐type (wt) mice, using high‐throughput  RNA  sequencing, revealed differential modulation of genes belonging to several  AMD ‐related pathogenic pathways, including inflammation, angiogenesis and extracellular matrix regulation. To investigate  AhR  regulation of these pathways in wet  AMD , we experimentally induced choroidal neovascular lesions in   AhR  −/−   mice and found that they measured significantly larger in area and volume compared to age‐matched wt mice. Furthermore, these lesions displayed a higher number of ionized calcium‐binding adaptor molecule 1‐positive (Iba1 + ) microglial cells and a greater amount of collagen type  IV  deposition, events also seen in human wet  AMD  pathology specimens. Consistent with our  in vivo  observations,   AhR   knock‐down was sufficient to increase choroidal endothelial cell migration and tube formation  in vitro . Moreover,   AhR   knock‐down caused an increase in collagen type  IV  production and secretion in both retinal pigment epithelial ( RPE ) and choroidal endothelial cell cultures, increased expression of angiogenic and inflammatory molecules, including vascular endothelial growth factor A (  VEGFA  ) and chemokine (C–C motif) ligand 2 (  CCL2  ) in  RPE  cells, and increased expression of secreted phosphoprotein 1 (  SPP1  ) and transforming growth factor‐ β 1 (  TGFβ1  ) in choroidal endothelial cells .  Collectively, our findings identify  AhR  as a regulator of multiple pathogenic pathways in experimentally induced choroidal neovascularization, findings that are consistent with a possible role of  AhR  in wet  AMD . The data discussed in this paper have been deposited in  NCBI 's Gene Expression Omnibus;  GEO  Submission No.  GSE56983 ,  NCBI  Tracking System No. 17021116. © 2014 The Authors.  The Journal of Pathology  published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Aryl hydrocarbon receptor knock‐out exacerbates choroidal neovascularization via multiple pathogenic pathways