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Exacerbation of autoimmune uveitis by obesity occurs through the melanocortin 5 receptor.

ABSTRACT: Autoimmune uveitis is a leading cause of blindness with a complex etiology. Obesity is considered a chronic disease with a connection with autoimmune diseases through systemic inflammation. However, an obesity and autoimmune disease connection is not consistently true in rodent models of autoimmune disease. A mouse model of human autoimmune uveitis, experimental autoimmune uveitis (EAU) has been used to better understand the immunobiology of uveitis. In this study, we assessed EAU in a high-fat diet (HFD) obesity model and found that the EAU severity is significantly higher in wild-type mice, but not in HFD melanocortin 5 receptor deficient mice. We find a decrease in CD11b+ F4/80+ Ly-6Clo Ly-6G+ M?s, previously shown to be suppressive, and an enhancement of a Th1 response at the onset of EAU in obese mice. We further demonstrate that at recovery of EAU, obese mice lack regulatory immunity that provides protection from EAU. This report demonstrates that obesity exacerbates autoimmune uveitis and inhibits the promotion of post-EAU regulatory immunity through the melanocortin 5 receptor. The implication of this work is that obesity may contribute to the prevalence of autoimmune uveitis.

SUBMITTER: Muhammad FY

PROVIDER: S-EPMC7304441 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Exacerbation of autoimmune uveitis by obesity occurs through the melanocortin 5 receptor.

Muhammad Fauziyya Y FY Peters Kayleigh K Wang Dawei D Lee Darren J DJ

Journal of leukocyte biology 20190709 4

Autoimmune uveitis is a leading cause of blindness with a complex etiology. Obesity is considered a chronic disease with a connection with autoimmune diseases through systemic inflammation. However, an obesity and autoimmune disease connection is not consistently true in rodent models of autoimmune disease. A mouse model of human autoimmune uveitis, experimental autoimmune uveitis (EAU) has been used to better understand the immunobiology of uveitis. In this study, we assessed EAU in a high-fat ...[more]

PMID: 31287586

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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

Exacerbation of autoimmune uveitis by obesity occurs through the melanocortin 5 receptor.

Publications

Exacerbation of autoimmune uveitis by obesity occurs through the melanocortin 5 receptor.

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