Down-regulation of aryl hydrocarbon receptor intensifies carcinogen-induced retinal lesion via SOCS3-STAT3 signaling.

The aryl hydrocarbon receptor (AHR) is a ligand-activated receptor that regulates the metabolism of several xenobiotics and participates in ocular inflammation. Although severe inflammation is a major risk of retinal damage, the underlying mechanism is not well established. In this study, to elucidate how AHR mediates inflammation homeostasis, we hypothesized that AHR expression may diminish during long-term exposure to benzo [a] pyrene (B [a]P), a carcinogen in cigarette smoke. The blockage of AHR function considerably impaired suppressor of cytokine signaling 3 (SOCS3) negative feedback regulation and upregulated B [a]P-induced pro-inflammation. Signal transducer and activator of transcription 3 was activated by B [a] P due to AHR dysfunction in human adult retinal pigment epithelial cells The element revealed higher activity in AHR knockout cells with B [a] P treatment, but not in wild type cells. Moreover, AHR dysfunction led to hypo-ubiquitination and changed the interaction. Increased duanyu18133-SOCS3 complex during AHR dysfunction by B [a] P was suppressed by nifuroxazide in duanyu37E-19 cells. Furthermore, the in vivo results showed that duanyu18133 inhibition during AHR impairment by long-term B [a] P exposure preserved the retina thickness and reversed the visual function in male C57Bl/6 mice. Overall, long-term B [a] P exposure may attenuate AHR function, dysregulating the homeostasis of the axis with intensive duanyu18133 activation. This finding is significant given that the disintegration of the AHR-SOCS3 axis is a sensitive factor involved in AMD-like lesion development in the retina, revealing that the low AHR level may be associated with cigarette smoking or xenobiotics exposure, causing retina inflammation and damage.

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