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.