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The Importance of Melanocortin Receptors and Their Agonists in Pulmonary Disease.

ABSTRACT: Melanocortin agonists are ancient neuropeptides that have steroidogenesis and anti-inflammatory properties. They activate melanocortin receptors (MCR), a family of five seven-transmembrane G-protein coupled receptors. MC1R and MC3R are mainly involved in immunomodulatory effects. Adrenocorticotropin hormone (ACTH) and alpha-Melanocortin stimulating hormone (?-MSH) reduce pro-inflammatory cytokines in several pulmonary inflammatory disorders including asthma, sarcoidosis, and the acute respiratory distress syndrome. They have also been shown to reduce fibrogenesis in animal models with pulmonary fibrosis. By understanding the functions of MCR in macrophages, T-helper cell type 1, and T-helper cell type 17, we may uncover the mechanism of action of melanocortin agonists in sarcoidosis. Further translational and clinical research is needed to define the role of ACTH and ?-MSH in pulmonary diseases.

SUBMITTER: Moscowitz AE

PROVIDER: S-EPMC6610340 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The Importance of Melanocortin Receptors and Their Agonists in Pulmonary Disease.

Moscowitz Anna Elizabeth AE Asif Huda H Lindenmaier Laurence Baily LB Calzadilla Andrew A Zhang Chongxu C Mirsaeidi Mehdi M

Frontiers in medicine 20190627

Melanocortin agonists are ancient neuropeptides that have steroidogenesis and anti-inflammatory properties. They activate melanocortin receptors (MCR), a family of five seven-transmembrane G-protein coupled receptors. MC1R and MC3R are mainly involved in immunomodulatory effects. Adrenocorticotropin hormone (ACTH) and alpha-Melanocortin stimulating hormone (α-MSH) reduce pro-inflammatory cytokines in several pulmonary inflammatory disorders including asthma, sarcoidosis, and the acute respirator ...[more]

PMID: 31316990

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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

The Importance of Melanocortin Receptors and Their Agonists in Pulmonary Disease.

Publications

The Importance of Melanocortin Receptors and Their Agonists in Pulmonary Disease.

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