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Small heat shock protein ?A-crystallin prevents photoreceptor degeneration in experimental autoimmune uveitis.

ABSTRACT: The small heat shock protein, ?A-crystallin null (?A-/-) mice are known to be more prone to retinal degeneration than the wild type mice in Experimental Autoimmune Uveoretinitis (EAU). In this report we demonstrate that intravenous administration of ?A preserves retinal architecture and prevents photoreceptor damage in EAU. Interestingly, only ?A and not ?B-crystallin (?B), a closely related small heat shock protein works, pointing to molecular specificity in the observed retinal protection. The possible involvement of ?A in retinal protection through immune modulation is corroborated by adaptive transfer experiments, (employing ?A-/- and wild type mice with EAU as donors and Rag2-/- as the recipient mice), which indicate that ?A protects against the autoimmune challenge by modulating the systemic B and T cell immunity. We show that ?A administration causes marked reduction in Th1 cytokines (TNF-?, IL-12 and IFN-?), both in the retina and in the spleen; notably, IL-17 was only reduced in the retina suggesting local intervention. Importantly, expression of Toll-like receptors and their associated adaptors is also inhibited suggesting that ?A protection, against photoreceptor loss in EAU, is associated with systemic suppression of both the adaptive and innate immune responses.

SUBMITTER: Rao NA

PROVIDER: S-EPMC3316578 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Small heat shock protein αA-crystallin prevents photoreceptor degeneration in experimental autoimmune uveitis.

Rao Narsing A NA Saraswathy Sindhu S Pararajasegaram Geeta G Bhat Suraj P SP

PloS one 20120330 3

The small heat shock protein, αA-crystallin null (αA-/-) mice are known to be more prone to retinal degeneration than the wild type mice in Experimental Autoimmune Uveoretinitis (EAU). In this report we demonstrate that intravenous administration of αA preserves retinal architecture and prevents photoreceptor damage in EAU. Interestingly, only αA and not αB-crystallin (αB), a closely related small heat shock protein works, pointing to molecular specificity in the observed retinal protection. The ...[more]

PMID: 22479415

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Project description:The melanocortin system plays an essential role in the regulation of immune activity. The anti-inflammatory microenvironment of the eye is dependent on the expression of the melanocortin-neuropeptide alpha-melanocyte stimulating hormone (α-MSH). In addition, the melanocortin system may have a role in retinal development and retinal cell survival under conditions of retinal degeneration. We have found that treating experimental autoimmune uveitis (EAU) with α-MSH suppresses retinal inflammation. Also, this augmentation of the melanocortin system promotes immune tolerance and protection of the retinal structure. The benefit of α-MSH-therapy appears to be dependent on different melanocortin receptors. Therefore, we treated EAU mice with α-MSH-analogs with different melanocortin-receptor targets. This approach demonstrated which melanocortin-receptors suppress inflammation, preserve retinal structure, and induce immune tolerance in uveitis. At the chronic stage of EAU the mice were injected twice 1 day apart with 50 μg of α-MSH or an α-MSH-analog. The α-MSH-analogs were a pan-agonist PL8331, PL8177 (potent MC1r-only agonist), PL5000 (a pan-agonist with no MC5r functional activity), MT-II (same as PL5000) and PG901 (MC5r agonist, but also an antagonist to MC3r, and MC4r). Clinical EAU scores were measured until resolution in the α-MSH-treated mice, when the eyes were collected for histology, and spleen cells collected for retinal-antigen-stimulated cytokine production. Significant suppression of EAU was seen with α-MSH or PL8331 treatment. This was accompanied with significant preservation of retinal structure. A similar effect was seen in EAU-mice that were treated with PL8177, except the suppression of EAU was temporary. In EAU mice treated with PL5000, MTII, or PG901, there was no suppression of EAU with a significant loss in whole retina and outer-nuclear layer thickness. There was significant suppression of IL-17 with induction of IL-10 by retinal-antigen stimulated spleen T cells from EAU mice treated with α-MSH, PL8331, PL8177, or PL5000, but not from EAU mice treated with MT-II, or PG901. Our previous studies show the melanocortin system's importance in maintaining ocular immune privilege and that α-MSH-treatment accelerates recovery and induces retinal-antigen-specific regulatory immunity in EAU. Our current results show that this activity is centered around MC1r and MC5r. In addition, the results suggest that a therapeutic potential to target MC1r and MC5r together to suppress uveitis induces regulatory immunity with potentially maintaining a normal retinal structure.

Dataset Information

Small heat shock protein ?A-crystallin prevents photoreceptor degeneration in experimental autoimmune uveitis.

Publications

Small heat shock protein αA-crystallin prevents photoreceptor degeneration in experimental autoimmune uveitis.

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