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      Melanocortin Receptors as Novel Effectors of Macrophage Responses in Inflammation

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          Abstract

          Macrophages have crucial functions in initiating the inflammatory reaction in a strict temporal and spatial manner to provide a “clear-up” response required for resolution. Hormonal peptides such as melanocortins modulate macrophage reactivity and attenuate inflammation ranging from skin inflammation to joint disease and reperfusion injury. The melanocortins (e.g., adrenocorticotrophin, ACTH and αMSH) elicit regulatory properties through activation of a family of GPCRs, the melanocortin (MC) receptors; MC 1–MC 5. Several studies have focused on MC 1 and MC 3 as anti-inflammatory receptors expressed on cells of the macrophage lineage. We review here elements of the melanocortin pathway with particular attention to macrophage function in anti-inflammatory and pro-resolving inflammatory settings. Evidence shows that ACTH, αMSH, and other MC agonists can activate MC 1 and MC 3 on macrophage through cAMP and/or NFκB-dependent mechanisms to abrogate pro-inflammatory cytokines, chemokines, and NO and enhance anti-inflammatory mediators such as IL-10 and HO-1. Melanocortins and their receptors regulate inflammation by inhibiting leukocyte recruitment to and interaction with inflamed tissue. An intensely exciting addition to this field of research has been the ability of an αMSH analog; AP214 to activate MC 3 expressed on macrophage to enhance their clearance of both zymosan particles and apoptotic neutrophils thus putting melanocortins in line with other pro-resolving mediators. The use of mouse colonies mutated or nullified for MC 1 or MC 3, respectively as well as availability of selective MC receptor agonist/antagonists have been key to deciphering mechanisms by which elements of the melanocortin system play a role in these phenomena. We review here melanocortin pathway components with attention to the macrophage, reiterating receptor targets required for pro-resolving properties. The overall outcome will be identification of selective MC agonists as a strategy for innovative anti-inflammatory therapeutics.

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          Most cited references42

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          A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse.

          The central melanocortin system is critical for the long term regulation of energy homeostasis. Null mutations of the melanocortin-4 receptor (MC4-R) are associated with hyperphagia, obesity, and accelerated longitudinal growth in mice and humans. However, little is known about the function of another central melanocortin receptor, the MC3-R. To assess the role of the MC3-R in energy homeostasis, the majority of the mc3r coding sequence was deleted from the mouse genome. In contrast to the MC4-R knockout, which exhibits increased food intake, increased somatic growth, and defects in metabolism, mc3r-/- mice exhibit an exclusively metabolic syndrome. Homozygous null mc3r mice, while not significantly overweight, exhibit an approximately 50% to 60% increase in adipose mass. Mc3r-/- mice also exhibit an unusual increase in respiratory quotient when transferred onto high fat chow, suggesting a reduced ratio of fat/carbohydrate oxidation. Furthermore, male mc3r-/- mice also exhibit an approximately 50% reduction in locomotory behavior on the running wheel, suggesting reduced energy expenditure.
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            The melanocortin system.

            The melanocortin system consists of melanocortin peptides derived from the proopiomelanocortin gene, five melanocortin receptors, two endogenous antagonists, and two ancillary proteins. This review provides an abbreviated account of the basic biochemistry, pharmacology, and physiology of the melanocortin system and highlights progress made in four areas. In particular, recent pharmacological and genetic studies have affirmed the role of melanocortins in pigmentation, inflammation, energy homeostasis, and sexual function. Development of selective agonists and antagonists is expected to further facilitate the investigation of these complex physiological functions and provide an experimental basis for new pharmacotherapies.
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              The Melanocortin System in Control of Inflammation

              Melanocortin peptides, the collective term for α-, β-, and γ-melanocyte-stimulating hormone (α-, β-, γ-MSH) and adrenocorticotropic hormone (ACTH), are elements of an ancient modulatory system. Natural melanocortins derive from the common precursor pro-opiomelanocortin (POMC). Five receptor subtypes for melanocortins (MC1-MC5) are widely distributed in brain regions and in peripheral cells. Melanocortin receptor activation by natural or synthetic ligands exerts marked anti-inflammatory and immunomodulatory effects. The anticytokine action and the inhibitory influences on inflammatory cell migration make melanocortins potential new drugs for treatment of inflammatory disorders. Effectiveness in treatment of acute, chronic, and systemic inflammatory disorders is well documented in preclinical studies. Further, melanocortins are promising compounds in neuroprotection. This review examines the main signaling circuits in anti-inflammatory and immunomodulatory actions of melanocortins, and the potential therapeutic use of these molecules.
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                Author and article information

                Journal
                Front Immunol
                Front Immunol
                Front. Immun.
                Frontiers in Immunology
                Frontiers Research Foundation
                1664-3224
                13 September 2011
                2011
                : 2
                : 41
                Affiliations
                [1] 1simpleWilliam Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London London, UK
                Author notes

                Edited by: Amiram Ariel, University of Haifa, Israel

                Reviewed by: Paola Allavena, Clinical Institute Humanitas, Italy; Anna Catania, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Italy

                *Correspondence: Hetal B. Patel, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. e-mail: h.b.patel@ 123456qmul.ac.uk

                This article was submitted to Frontiers in Inflammation, a specialty of Frontiers in Immunology.

                Article
                10.3389/fimmu.2011.00041
                3342072
                22566831
                c08018b2-e240-4c57-a95e-37b25e971d41
                Copyright © 2011 Patel, Montero-Melendez, Greco and Perretti.

                This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and other Frontiers conditions are complied with.

                History
                : 30 June 2011
                : 22 August 2011
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 41, Pages: 6, Words: 5160
                Categories
                Immunology
                Mini Review Article

                Immunology
                anti-inflammatory therapeutics,melanocortins,macrophage,g-protein coupled receptor,melanocortin receptor,inflammation,resolution,melanocyte stimulating hormone

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