Aryl hydrocarbon receptor modulates dysregulatory inflammatory responses in human retinal pigment epithelial cells.

Abstract

Blue light-induced retinopathy is a sight-threatening condition which leads to chronic parainflammation, in which retinal pigment epithelium (RPE) dysfunction plays a critical role. While the complement system and the inflammatory cytokine IL-17A are implicated in its pathogenesis, their precise interplay within the RPE, along with the role of the immunomodulatory aryl hydrocarbon receptor (AhR), remains unclear. To address this gap, we investigated the interaction between AhR, the complement system, and IL-17A in RPE inflammation using an in vivo mouse model involving chronic low-intensity blue light exposure (300 Lux, 12 h/day for 35 days) and an in vitro system with human ARPE-19 cells (wild-type and AhR-knockout). We found that blue light exposure increased retinal C3, C5, and IL-17A while downregulating AhR. In cell cultures, treatment with C3a, C5a, or IL-17A triggered the expression of inflammatory and angiogenic factors, an effect that was significantly amplified in AhR-knockout cells through increased C3a and IL-8 expression. This heightened inflammatory response was mediated by enhanced NF-κB signaling, associated with defective p65 dephosphorylation by WIP1. These findings reveal a novel regulatory axis where AhR suppresses complement- and IL-17A-driven inflammation, highlighting it as a key hub for regulating blue light-induced retinopathy.