Aryl Hydrocarbon Receptor Regulates Apoptosis and Inflammation in a Murine Model of Experimental Autoimmune Uveitis

Abstract

Uveitis is characterized as a common cause of blindness worldwide. Aryl hydrocarbon receptor (AhR), a ligand-activated nuclear receptor, has been implicated to play a role in human uveitis, although the exact mechanisms remain poorly understood. The purpose of this study was to enhance our knowledge concerning the role of AhR during intraocular inflammation. We immunized wild-type and AhR-knockout C57BL/6J mice with IRBP651–670 to induce experimental autoimmune uveitis (EAU). Disease severity was evaluated with both clinical and histopathological grading. Blood–retinal barrier (BRB) integrity was tested by Evans blue and tight junction proteins qualifications. Apoptosis was measured using TdT-mediated dUTP nick end labeling staining. Macrophage/microglia activation and polarization were studied by immunofluorescence and Western blot. Following EAU induction, AhR−/− mice had more severe clinical and histopathological manifestations of uveitis than AhR+/+ mice. Increased vascular permeability and apoptotic cells were observed in AhR−/− EAU mice when compared with AhR+/+ EAU mice. In addition, AhR−/− EAU mice showed evidence of a significantly increased macrophage/microglia cells and a stronger polarization from the M2 to the M1 phenotype as compared to AhR+/+ EAU mice. The levels of pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β were increased in AhR−/− EAU mice, which was associated with the activation of NF-κB and signal transducers and activators of transcription (STAT) pathways. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an agonist of AhR, caused a significant decrease in the clinical and histopathological manifestations, preserved BRB integrity, reduced apoptotic cells, inhibited macrophage/microglia activation, and shifted their polarization from M1 toward M2. Moreover, decreased expression of pro-inflammatory cytokines including TNF-α, IL-6, and IL-1β and inhibition of NF-κB and STAT pathways were found in EAU mice following TCDD treatment. In conclusion, AhR activation with TCDD exhibits an immunomodulatory effect by reducing BRB breakdown, inhibiting retinal cell apoptosis, and reducing pro-inflammatory cytokine expression during EAU. The underlying mechanism may involve the modulation of macrophages/microglia polarization and the downregulation of NF-κB and STAT pathways.

Indole-3-carbinol regulates microglia homeostasis and protects the retina from degeneration

“…Thus, I3C prevented ischemic reperfusion-induced inflammation and improved neurobehavioral symptoms in a cerebral ischemic stroke model [ 41 , 42 ]. AhR agonists also reversed pro-inflammatory gene expression in experimental autoimmune uveitis [ 11 ]. Here, we found that I3C prevented light-induced CCL2 expression in the retina.…”

“…In the ocular compartment, AhR knockout triggers apoptosis and inflammation in experimental autoimmune uveitis [ 11 ]. AhR deficiency also disturbs extracellular matrix biology, leading to an AMD-like pathology in mice [ 12 ].…”

The Aryl Hydrocarbon Receptor: A Mediator and Potential Therapeutic Target for Ocular and Non-Ocular Neurodegenerative Diseases

“…Treatment with AHR agonists, 6-formylindolo(3,2-b)carbazole (FICZ) and 2-(1'H-indole-3'carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), can inhibit interferon-gamma (IFN-γ), interleukn-17 (IL-17), and induced IL-22 production by PBMCs, leading to a decrease in overall inflammation. Similarly, AHR activation has shown therapeutic effects in an experimental model of uveitis, which is an intraocular inflammatory disease [128,129]. It has also been shown that the AHR is involved in regulating apoptosis and inflammation in experimental autoimmune uveitis (EAU).…”

“…It has also been shown that the AHR is involved in regulating apoptosis and inflammation in experimental autoimmune uveitis (EAU). Ahr −/− mice subjected to EAU show evidence of significantly increased macrophage presence and stronger polarization from the M2 (involved in tissue repair) to the M1 (proinflammatory) phenotype compared to Ahr +/+ mice [129]. Ahr −/− EAU mice also display higher protein expression levels of the M1 marker subset, inducible nitric oxide synthase (iNOS) and CD16, and lower protein expression levels of the M2 marker subset, arginase-1 (Arg-1) and CD206, relative to Ahr +/+ EAU mice [129].…”

Dietary natural flavonoids treating cancer by targeting aryl hydrocarbon receptor

“…In AhR À/À mice, the incidence of liver cancer induced by diethylnitrosamine (non-AhR ligand) was higher than that in wild-type (AhR þ/þ ) mice, because high levels of oxidative stress and stable expression of TGF-B promoted tumor development in AhR À/À male mice (Fan et al 2010). Huang, YK et al discovered that after experimental autoimmune uveitis induction, AhR À/À mice had more severe clinical and histopathological findings of uveitis than AhR þ/þ mice (Huang et al 2018). More recently, Iu et al found that AhR can inhibit inflammation, oxidative stress and apoptosis caused by cigarette smoke through mechanisms involved in RelB gene (NF-B member) regulation (Iu et al 2017).…”