Aryl hydrocarbon receptor deficiency upregulates intercellular adhesion molecule 1 in retinal pigment epithelial cells and contributes to retinal inflammation.

Retinal pigment epithelium (RPE) cells, located between the photoreceptors and choroid, play a crucial role in maintaining retinal health and function. They act as immunosuppressive barriers, preventing immune cell infiltration from the choroid. Retinal inflammation contributes to the development of various ocular diseases. The aryl hydrocarbon receptor (AHR) is a well-established ligand-dependent transcription factor that mediates potent anti-inflammatory signals following ligand binding. AHR expression is notably reduced under several conditions that negatively affect the retina. We hypothesized that AHR protein loss may impairs RPE cell function, shifting them toward a pro-inflammatory phenotype. In this study, we investigated the pro-inflammatory pathways activated by AHR knockout (AHR-KO) and examined associated retinal phenotypic changes in AHR-KO mice. Our findings suggest that AHR deficiency may enhance the activity of αvβ3-integrin, extracellular signal-regulated kinases (ERK1/2), and p65 subunit of nuclear factor kappa B (NF-κB), leading to an upregulation of intercellular adhesion molecule 1 (ICAM1) and promoting monocyte adhesion in vitro. Introducing an AHR-green fluorescent protein into AHR-KO RPE cells or pre-treating the cells with pharmacological inhibitors targeting αvβ3 (cycloRGDfk), focal adhesion kinase (PF573228), phospholipase C (U73122), ERK1/2 (U0126), and NF-κB (Bay11-7082) prevented ICAM1 induction in AHR-KO RPE cells. These results suggest that the pro-inflammatory pathway is driven by AHR deficiency. In AHR-KO mice, retinal tissues showed ICAM1 accumulation, microglial activation, and migration, indicating chronic retinal inflammation due to AHR deficiency. These mice also displayed early-onset electroretinogram degeneration. Collectively, our data support the protective role of AHR in maintaining RPE cell physiology and retinal health.