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 (STAT3) was activated by B [a] P due to AHR dysfunction in human adult retinal pigment epithelial cells (ARPE-19). The STAT3-inducible element revealed higher activity in AHR knockout cells with B [a] P treatment, but not in wild type ARPE-19 cells. Moreover, AHR dysfunction led to STAT3 hypo-ubiquitination and changed the STAT3–SOCS3 interaction. Increased STAT3–SOCS3 complex during AHR dysfunction by B [a] P was suppressed by nifuroxazide in ARPE-19 cells. Furthermore, the in vivo results showed that STAT3 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 SOCS3–STAT3 axis with intensive STAT3 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.

中文翻译：

---

芳烃受体的下调通过 SOCS3-STAT3 信号传导加剧致癌物诱导的视网膜病变。

芳烃受体 (AHR) 是一种配体激活受体，可调节几种异生物质的代谢并参与眼部炎症。尽管严重的炎症是视网膜损伤的主要风险，但其潜在机制尚不明确。在这项研究中，为了阐明 AHR 如何介导炎症稳态，我们假设 AHR 表达可能在长期接触香烟烟雾中的致癌物质苯并 [a] 芘 (B [a] P) 期间减少。AHR 功能的阻断显着损害了细胞因子信号传导 3 (SOCS3) 负反馈调节的抑制作用，并上调了 B [a] P 诱导的促炎症反应。由于人成人视网膜色素上皮细胞 (ARPE-19) 中的 AHR 功能障碍，信号转导和转录激活因子 3 (STAT3) 被 B [a] P 激活。STAT3 诱导元件在 B [a] P 处理的 AHR 敲除细胞中显示出更高的活性，但在野生型 ARPE-19 细胞中没有。此外，AHR 功能障碍导致 STAT3 低泛素化并改变 STAT3-SOCS3 相互作用。在 AHR 功能障碍期间 B [a] P 增加的 STAT3-SOCS3 复合物被 ARPE-19 细胞中的硝呋噻嗪抑制。此外，体内结果表明，长期 B [a] P 暴露在 AHR 损伤期间的 STAT3 抑制保留了雄性 C57Bl/6 小鼠的视网膜厚度并逆转了视觉功能。总体而言，长期 B [a] P 暴露可能会减弱 AHR 功能，从而通过强烈的 STAT3 激活失调 SOCS3-STAT3 轴的稳态。鉴于 AHR-SOCS3 轴的解体是参与视网膜 AMD 样病变发展的敏感因素，这一发现意义重大，