Aldose reductase deficiency protects from autoimmune- and endotoxin-induced uveitis in mice.

Abstract

PURPOSE:

To investigate the effect of aldose reductase (AR) deficiency in protecting the chronic experimental autoimmune (EAU) and acute endotoxin-induced uveitis (EIU) in c57BL/6 mice.

METHODS:

The WT and AR-null (ARKO) mice were immunized with human interphotoreceptor retinoid-binding peptide (hIRPB-1-20), to induce EAU, or were injected subcutaneously with lipopolysaccharide (LPS; 100 μg) to induce EIU. The mice were killed on day 21 for EAU and at 24 hours for EIU, when the disease was at its peak, and the eyes were immediately enucleated for histologic and biochemical studies. Spleen-derived T-lymphocytes were used to study the antigen-specific immune response in vitro and in vivo.

RESULTS:

In WT-EAU mice, severe damage to the retinal wall, especially to the photoreceptor layer was observed, corresponding to a pathologic score of ∼2, which was significantly prevented in the ARKO or AR inhibitor-treated mice. The levels of cytokines and chemokines increased markedly in the whole-eye homogenates of WT-EAU mice, but not in ARKO-EAU mice. Further, expression of inflammatory marker proteins such as inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α, and vascular cell adhesion molecule (VCAM)-1 was increased in the WT-EIU mouse eyes but not in the ARKO-EIU eyes. The T cells proliferated vigorously when exposed to the hIRPB antigen in vitro and secreted various cytokines and chemokines, which were significantly inhibited in the T cells isolated from the ARKO mice.

CONCLUSIONS:

These findings suggest that AR-deficiency/inhibition protects against acute as well as chronic forms of ocular inflammatory complications such as uveitis.

• Authors: Umesh C S Yadav, Mohammed Shoeb, Satish K Srivastava, Kota V Ramana
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 52 Issue 11 Pg. 8076-85 (Oct 17 2011) ISSN: 1552-5783 [Electronic] United States
• PMID: 21911582 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Chemokines
• Cytokines
• Enzyme Inhibitors
• Eye Proteins
• Imidazolidines
• Lipopolysaccharides
• NF-kappa B
• Reactive Oxygen Species
• Retinol-Binding Proteins
• interstitial retinol-binding protein
• Nitric Oxide
• fidarestat
• Aldehyde Reductase
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse
• Cyclooxygenase 2

Topics

• Adoptive Transfer
• Aldehyde Reductase (antagonists & inhibitors)
• Animals
• Aqueous Humor (metabolism)
• Autoimmune Diseases (chemically induced, enzymology, pathology, prevention & control)
• Blotting, Western
• Cells, Cultured
• Chemokines (metabolism)
• Cyclooxygenase 2 (metabolism)
• Cytokines (metabolism)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Eye Proteins (toxicity)
• Fluorescent Antibody Technique, Indirect
• Imidazolidines (pharmacology)
• Leukocytes (physiology)
• Lipopolysaccharides (toxicity)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B (metabolism)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type II (metabolism)
• Reactive Oxygen Species (metabolism)
• Retinol-Binding Proteins (toxicity)
• T-Lymphocytes (immunology)
• Uveitis (chemically induced, enzymology, pathology, prevention & control)