Melanocortin Receptors as Novel Effectors of Macrophage Responses in Inflammation

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; MC1–MC5. Several studies have focused on MC1 and MC3 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 MC1 and MC3 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 MC3 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 MC1 or MC3, 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.

Pharmacological Activation of the Melanocortin System Limits Plaque Inflammation and Ameliorates Vascular Dysfunction in Atherosclerotic Mice

“…These findings are supported by other studies proving that pharmacological targeting of MC-Rs suppresses the secretion of proinflammatory mediators by macrophages and induces M2 polarization in experimental models of inflammatory disease. 10,32,33 Consistent with the finding of decreased 18 F-FDG signal and altered macrophage phenotype, we demonstrate that the systemic inflammation profile was favorably modified in MT-II-treated mice. Specifically, MT-II treatment was able suppress the plasma levels of interleukin-1β and interleukin-6, which are considered as proinflammatory mediators promoting atherosclerosis.…”

Neuropeptides and Microglial Activation in Inflammation, Pain, and Neurodegenerative Diseases

“…This system is also tightly linked to control of inflammation, both centrally and peripherally, by exerting anti-inflammatory actions on cells of the immune system including lymphocytes, monocytes, and macrophages, as well as nonimmune cells such as melanocytes, keratinocytes, and adipocytes, among others [22]. Melanocortins may also regulate macrophage differentiation into tissue-specific cells such as osteoclasts, Kupffer cells, and microglia [23], further highlighting the role of these neuropeptides as modulators of immunity.…”

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

“…There are several subtypes of the melanocortin peptides, such as adrenocorticotrophin (ACTH) and alpha-melanocyte-stimulating hormone (α-MSH), which act at G-protein-coupled melanocortin receptors such as the MC 1-5 receptors [118,138,139]. In the brain, POMC is mainly expressed in the Arc [138,140], and projects to various regions of the hypothalamus [118,141].…”