Melanocortin receptors as novel effectors of macrophage responses in inflammation
1 - 6
Frontiers in Immunology
MetadataShow full item record
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 in a variety of settings from skin inflammation to joint disease and post-reperfusion injury. The melanocortins (e.g. ACTH and αMSH) elicit regulatory properties through activation of a family of GPCRs, the 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 settings. A growing body of 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 nitric oxide and enhance anti-inflammatory mediators such as IL-10 and hemeoxygenase-1. Melanocortins and their receptors participate in resolution of 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 analogue; 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 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 elements of the melanocortin pathway with particular attention to the macrophage, reiterating receptor targets required for pro-resolving properties. The overall outcome will be identification of selective MC3 agonists as a strategy for innovative anti-inflammatory therapeutics.
AuthorsPatel, HB; Montero-Melendez, T; Greco, KV; Perretti, M
- College Publications