Decreased Expression of the Aryl Hydrocarbon Receptor in Ocular Behcet’s Disease

Wang, Chaokui; Ye, Zi; Kijlstra, Aize; Zhou, Yan; Yang, Peizeng

doi:10.1155/2014/195094

Cited by 13 publications

(11 citation statements)

References 35 publications

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“…In the experimental model of age-related macular degeneration, AhR −/− mice exhibited subretinal accumulation of microglia and exacerbated choroidal neovascularization ( 28 , 29 ). A previous study from our group showed that a decreased AhR expression is associated with disease activity in Behcet’s disease patients ( 30 ). A recent study suggested that AhR activation by TCDD was able to suppress EAU by inducing regulatory T cells ( 31 ).…”

Section: Introductionmentioning

confidence: 92%

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

Huang

Liang

et al. 2018

Front. Immunol.

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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.

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Section: Introductionmentioning

confidence: 92%

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

Huang

Liang

et al. 2018

Front. Immunol.

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“…Exposure to AHR-activating toxicants has been reported to contribute to the development of immune disorders and given that the AHR plays a critical role in regulating immune responses, it is important to discuss the interactions between the AHR pathway and the pathogenesis of inflammatory disorders with ocular indications [54,122,123]. AHR message levels have been found to be reduced in peripheral blood mononuclear cells and macrophages isolated from patients of Behcet's disease, which is a chronic systemic inflammatory disease affecting the eye, skin, oral, mucosa, gastrointestinal tract and central nervous system [124][125][126]. The AHR has also been shown to regulate inflammation via the STAT3-SOCS3 pathway, leading to retinopathy in Ahr −/− mice, as a result of carcinogen, benzo(a)pyrene treatment.…”

Section: The Ahr and Ocular Diseasesmentioning

confidence: 99%

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

Choudhary

Malek

2020

IJMS

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The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, which senses environmental, dietary or metabolic signals to mount a transcriptional response, vital in health and disease. As environmental stimuli and metabolic products have been shown to impact the central nervous system (CNS), a burgeoning area of research has been on the role of the AHR in ocular and non-ocular neurodegenerative diseases. Herein, we summarize our current knowledge, of AHR-controlled cellular processes and their impact on regulating pathobiology of select ocular and neurodegenerative diseases. We catalogue animal models generated to study the role of the AHR in tissue homeostasis and disease pathogenesis. Finally, we discuss the potential of targeting the AHR pathway as a therapeutic strategy, in the context of the maladies of the eye and brain.

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“…To the best of our knowledge, this is the first study that reveals the critical contribution of AhR deficiency to the IC-mediated disease model, except for collagen-induced arthritis. Similarly, decreased AhR expression in peripheral blood mononuclear cells is also observed in patients with Behçet's disease (Wang et al, 2014b). In addition, lipopolysaccharide-treated DCs from active patients with Behçet's disease showed a higher level of inflammatory cytokine production (Wang et al, 2014a).…”

Section: Discussionmentioning

confidence: 91%

Exacerbated Immune Complex-Mediated Vascular Injury in Mice with Heterozygous Deficiency of Aryl Hydrocarbon Receptor through Upregulation of Fcγ Receptor III Expression on Macrophages

Nakajima

Miyagaki

Morimura

et al. 2018

Journal of Investigative Dermatology

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Aryl hydrocarbon receptor (AhR), which was discovered as a receptor for environmental concomitants, plays an important role widely in the immune system. In this study, we assessed AhR involvement in immune-complex-mediated vascular injury by examining the reverse-passive Arthus reaction in AhR heterozygous knockout (AhR) mice. In the cutaneous Arthus reaction, dermal edema was severer in AhR mice than in wild-type mice. The number of infiltrating neutrophils and mRNA expression levels of CXC chemokine ligand 1 and IL-6 were also increased in AhR mice. Similarly, in the peritoneal Arthus reaction, infiltration of neutrophils was increased in AhR mice. Peritoneal macrophages from AhR mice expressed higher levels of Fcγ receptor III and produced higher levels of CXC chemokine ligand 1 and IL-6 after immune complex treatment. In addition, AhR occupied the promoter regions of Fcγ receptor III gene in peritoneal macrophages in a ligand-dependent manner. Depletion of macrophages reduced the cutaneous Arthus reaction in AhR mice, and adoptive transfer of AhR mice macrophages into wild-type mice exacerbated the peritoneal Arthus reaction. Furthermore, AhR expression was decreased and Fcγ receptor III expression was increased in CD14 monocytes in peripheral blood from patients with immune-complex-mediated vasculitis compared with those from healthy controls. These results suggest that downregulation of AhR is associated with the exacerbation of immune-complex-mediated vascular injury.

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Decreased Expression of the Aryl Hydrocarbon Receptor in Ocular Behcet’s Disease

Cited by 13 publications

References 35 publications

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

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

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

Exacerbated Immune Complex-Mediated Vascular Injury in Mice with Heterozygous Deficiency of Aryl Hydrocarbon Receptor through Upregulation of Fcγ Receptor III Expression on Macrophages

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