Retinal degeneration is a leading cause of visual impairment and blindness worldwide. Microglia reactivity is a hallmark of neurodegenerative diseases and a driving force for retinal cell death and disease progression. Thus, immunomodulation emerges as a potential therapeutic option. AhR deficiency is known to trigger inflammation and previous studies revealed important roles for AhR ligands in neuroprotection without focusing on microglia. Here, we investigate the anti-inflammatory and antioxidant effects of the synthetic aryl hydrocarbon receptor (AhR) ligand 2, 2′-aminophenyl indole (2AI) on microglia reactivity. We showed that 2AI potently reduced pro-inflammatory gene expression and induced antioxidant genes in activated human and murine microglia cells, in LPS-stimulated retinal explants as well as in stressed human ARPE-19 cells. 2AI also diminished LPS-induced nitric oxide (NO) release, their neurotoxic activity on photoreceptor cells, phagocytosis, and migration in murine BV-2 cells as important functional microglia parameters. siRNA-mediated knockdown of AhR partially prevented the previously observed gene regulatory effects in BV-2 cells. Our results show for the first time, that the synthetic AhR agonist 2AI regulates microglia homeostasis, highlighting AhR as a potential drug target for immunomodulatory and antioxidant therapies.

视网膜变性是全世界视力障碍和失明的主要原因。小胶质细胞反应性是神经退行性疾病的标志，也是视网膜细胞死亡和疾病进展的驱动力。因此，免疫调节成为一种潜在的治疗选择。众所周知，AhR 缺乏会引发炎症，之前的研究揭示了 AhR 配体在神经保护中的重要作用，而无需关注小胶质细胞。在这里，我们研究了合成芳烃受体 (AhR) 配体 2, 2'-氨基苯基吲哚 (2AI) 对小胶质细胞反应性的抗炎和抗氧化作用。我们表明，2AI 可有效降低活化的人和鼠小胶质细胞、LPS 刺激的视网膜外植体以及受压的人类 ARPE-19 细胞中的促炎基因表达并诱导抗氧化基因。2AI 还减少了 LPS 诱导的一氧化氮 (NO) 释放、它们对感光细胞的神经毒性活性、吞噬作用和鼠 BV-2 细胞中作为重要功能性小胶质细胞参数的迁移。siRNA 介导的 AhR 组合式部分阻止了先前在 BV-2 细胞中观察到的基因调控效应。我们的研究结果首次表明，合成的 AhR 激动剂 2AI 可调节小胶质细胞的稳态，突出了 AhR 作为免疫调节和抗氧化疗法的潜在药物靶点。