[D-Trp8]-gamma-melanocyte-stimulating hormone exhibits anti-inflammatory efficacy in mice bearing a nonfunctional MC1R (recessive yellow e/e mouse)

Two melanocortin receptors (MC1 and MC3R) have been identified as main transducers of the anti-inflammatory effects of natural and synthetic melanocortins. In this study, we have taken advantage of the recent description of the selective MC3R agonist [d-Trp(8)]-gamma-melanocyte-stimulating hormone (MSH) and of the recessive yellow (e/e) mouse, bearing a nonfunctional MC1R, thereby incrementing our knowledge on this topic. Culturing peritoneal macrophages of recessive yellow (e/e) mice with [d-Trp(8)]-gamma-MSH led to accumulation of cAMP, indicating MC3R receptor functionality: this effect was blocked by a neutralizing antibody against MC3R. Likewise, release of the chemokine KC by urate crystals was attenuated by [d-Trp(8)]-gamma-MSH, and this effect was prevented by synthetic [Ac-Nle(4)-c[Asp(5)-2'-Nal(7),Lys(10)]alpha-MSH(4-10)-NH(2) (SHU9119)] and natural [agouti-related protein (AGRP)] MC3R antagonists but not by the MC4R antagonist Ac-Cys-Nle-Arg-His-d-2-Nal-Arg-Trp-Cys-NH(2) (HS024). Systemic treatment of mice with [d-Trp(8)]-gamma-MSH inhibited KC release and polymorphonuclear cell accumulation elicited by urate crystals in the murine peritoneal cavity. SHU9119 and AGRP prevented the inhibitory actions of [d-Trp(8)]-gamma-MSH, whereas HS024 was inactive. We also demonstrate here that [d-Trp(8)]-gamma-MSH displays a dual mechanism of action by inducing the anti-inflammatory protein heme-oxygenase 1 (HO-1). Treatment with the HO-1 inhibitor zinc protoporphyrin IX exacerbated the inflammatory response elicited by urate crystals and abrogated the anti-inflammatory effects of [d-Trp(8)]-gamma-MSH. In conclusion, these data support the development of the selective MC3R agonist [d-Trp(8)]-gamma-MSH for the treatment of inflammatory pathologies, based on a dual mechanism of cytokine/chemokine inhibition and induction of the anti-inflammatory protein HO-1.