Oxidative photoreceptor cell damage in autoimmune uveitis

Nguyen, Angeline; Rao, Narsing A.

doi:10.1007/s12348-010-0007-5

Cited by 18 publications

(19 citation statements)

References 33 publications

(70 reference statements)

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“…We observed that TCDD treatment suppressed the levels of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β. This anti-inflammatory effect of TCDD may be due to its modulation of macrophages/microglia, as the activated M1 subset accelerates inflammation and causes tissue damage by increasing the secretion of multiple pro-inflammatory cytokines such as TNF-α, IL-6, and the release of reactive oxygen species, resulting in the nitration of cytochrome c which is known to cause apoptosis ( 7 , 17 , 18 ). These findings indicate that the anti-inflammatory effect of AhR may contribute to its protection on BRB as well as the control of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…Although safer, this strategy would not completely eliminate the risk. Sympathetic ophthalmia is a rare disease in which surgery or injury to one eye incites an immune reaction that causes an inflammatory injury to the patient’s contralateral or sympathetic eye 69 70 . Despite aggressive immune suppression, some cases of sympathetic ophthalmia can result in irreversible blindness 71 .…”

Section: Discussionmentioning

confidence: 99%

cGMP production of patient-specific iPSCs and photoreceptor precursor cells to treat retinal degenerative blindness

Wiley

Burnight

DeLuca

et al. 2016

Sci Rep

102

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Immunologically-matched, induced pluripotent stem cell (iPSC)-derived photoreceptor precursor cells have the potential to restore vision to patients with retinal degenerative diseases like retinitis pigmentosa. The purpose of this study was to develop clinically-compatible methods for manufacturing photoreceptor precursor cells from adult skin in a non-profit cGMP environment. Biopsies were obtained from 35 adult patients with inherited retinal degeneration and fibroblast lines were established under ISO class 5 cGMP conditions. Patient-specific iPSCs were then generated, clonally expanded and validated. Post-mitotic photoreceptor precursor cells were generated using a stepwise cGMP-compliant 3D differentiation protocol. The recapitulation of the enhanced S-cone phenotype in retinal organoids generated from a patient with NR2E3 mutations demonstrated the fidelity of these protocols. Transplantation into immune compromised animals revealed no evidence of abnormal proliferation or tumor formation. These studies will enable clinical trials to test the safety and efficiency of patient-specific photoreceptor cell replacement in humans.

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“…From multiple studies conducted in rodent EAU, backed by research using diseased human eyes, an important role for oxidative stress in posterior uveitis has been recognized (Nguyen and Rao, 2011; Rao, 1990). A key player is nitric oxide, which is produced from arginine and oxygen through the action of inducible nitric oxide synthase (NOS2) or constitutively expressed neuronal (NOS1) and endothelial (NOS3) forms (Lowenstein et al, 1994).…”

Section: Autoimmune Posterior Uveitismentioning

confidence: 99%

Role of the retinal vascular endothelial cell in ocular disease

Bharadwaj

Appukuttan

Wilmarth

et al. 2013

Progress in Retinal and Eye Research

136

114

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Retinal endothelial cells line the arborizing microvasculature that supplies and drains the neural retina. The anatomical and physiological characteristics of these endothelial cells are consistent with nutritional requirements and protection of a tissue critical to vision. On the one hand, the endothelium must ensure the supply of oxygen and other nutrients to the metabolically active retina, and allow access to circulating cells that maintain the vasculature or survey the retina for the presence of potential pathogens. On the other hand, the endothelium contributes to the blood-retinal barrier that protects the retina by excluding circulating molecular toxins, microorganisms, and pro-inflammatory leukocytes. Features required to fulfill these functions may also predispose to disease processes, such as retinal vascular leakage and neovascularization, and trafficking of microbes and inflammatory cells. Thus, the retinal endothelial cell is a key participant in retinal ischemic vasculopathies that include diabetic retinopathy and retinopathy of prematurity, and retinal inflammation or infection, as occurs in posterior uveitis. Using gene expression and proteomic profiling, it has been possible to explore the molecular phenotype of the human retinal endothelial cell and contribute to understanding of the pathogenesis of these diseases. In addition to providing support for the involvement of well-characterized endothelial molecules, profiling has the power to identify new players in retinal pathologies. Findings may have implications for the design of new biological therapies. Additional progress in this field is anticipated as other technologies, including epigenetic profiling methods, whole transcriptome shotgun sequencing, and metabolomics, are used to study the human retinal endothelial cell.

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Oxidative photoreceptor cell damage in autoimmune uveitis

Cited by 18 publications

References 33 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

cGMP production of patient-specific iPSCs and photoreceptor precursor cells to treat retinal degenerative blindness

Role of the retinal vascular endothelial cell in ocular disease

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