The AhR ligand 2, 2′-aminophenyl indole (2AI) regulates microglia homeostasis and reduces pro-inflammatory signaling

https://doi.org/10.1016/j.bbrc.2021.09.054Get rights and content
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Highlights

  • The synthetic AhR agonist 2AI reduced microglia activation and neurotoxicity.

  • 2AI enhanced antioxidant gene expression and reduced microglia neurotoxicity.

  • 2AI modulated functional microglia parameters such as phagocytosis and migration.

  • Anti-inflammatory and anti-oxidant effects of 2AI depend on AhR expression.

Abstract

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.

Keywords

Microglia
2AI
Aryl hydrocarbon receptor
Retina
Inflammation
Antioxidants

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These authors contributed equally.