Dataset Information

MicroRNA-146a Alleviates Experimental Autoimmune Anterior Uveitis in the Eyes of Lewis Rats.

ABSTRACT: This study aimed to determine the effect and roles of microRNA (miRNA, miR) treatment in experimental autoimmune anterior uveitis (EAAU).Uveitis was induced in Lewis rats by simultaneous injections of bovine melanin-associated antigen into the hind footpad and the intraperitoneal cavity. The animals were injected intravitreally with low-dose (0.5??g) or high-dose (1.5??g) miR-146a. The clinical scores, leukocyte count in the aqueous humor, and histology were assessed. Cytokine changes were evaluated by relative mRNA expression and enzyme-linked immunosorbent assay (ELISA). The expression of nuclear factor kappa B (NF-?B) was assessed by immunofluorescence and Western blotting. Evaluation of the DNA-binding activity of NF-?B was performed by electrophoretic mobility shift assay (EMSA).Treatment with miR-146a significantly attenuated clinical scores and leukocyte infiltration in a dose-dependent manner, a result that was compatible with histological findings. Following miR-146a injections, downregulation of interleukin- (IL-) 1?, IL-6, and IL-12 and interferon- (IFN-) ? and upregulation of IL-10 and IL-17 were noted. The decreased NF-?B expression on immunofluorescence and Western blotting and reduced DNA-binding activity on EMSA were demonstrated following miR-146a treatment.miR-146a effectively reduced intraocular inflammation in EAAU through the inhibition of NF-?B. miR-146a might be a new treatment choice for uveitis.

SUBMITTER: Hsu YR

PROVIDER: S-EPMC5757132 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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MicroRNA-146a Alleviates Experimental Autoimmune Anterior Uveitis in the Eyes of Lewis Rats.

Hsu Yung-Ray YR Chang Shu-Wen SW Lin Yu-Cheng YC Yang Chang-Hao CH

Mediators of inflammation 20171224

<h4>Purpose</h4>This study aimed to determine the effect and roles of microRNA (miRNA, miR) treatment in experimental autoimmune anterior uveitis (EAAU).<h4>Materials and methods</h4>Uveitis was induced in Lewis rats by simultaneous injections of bovine melanin-associated antigen into the hind footpad and the intraperitoneal cavity. The animals were injected intravitreally with low-dose (0.5 <i>μ</i>g) or high-dose (1.5 <i>μ</i>g) miR-146a. The clinical scores, leukocyte count in the aqueous hum ...[more]

PMID: 29434444

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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

MicroRNA-146a Alleviates Experimental Autoimmune Anterior Uveitis in the Eyes of Lewis Rats.

Publications

MicroRNA-146a Alleviates Experimental Autoimmune Anterior Uveitis in the Eyes of Lewis Rats.

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