The role of melanocortin-1 and -3 receptors in inflammation and atherosclerosis

Abstract

The melanocortin system comprises the endogenous melanocortin peptides adrenocorticotropic hormone (ACTH) and melanocyte-stimulating hormones (α-, β- & γ-MSH) as well as their five cognate receptors (MC1R – MC5R). These peptides are post-translational products of the proopiomelanocortin precursor hormone and mediate multiple biological processes including skin pigmentation, energy homeostasis and inflammation. Melanocortins elicit potent anti-inflammatory actions by activating MC1R and MC3R, which are widely expressed in different leukocyte subsets. Atherosclerosis is a chronic inflammatory disease characterized by lipid and leukocyte accumulation in arterial walls that leads to the development of atherosclerotic plaques and eventually to acute complications such as stroke and myocardial infarction. Melanocortins have been previously shown to suppress inflammation in experimental atherosclerosis. The primary aim of this thesis was to investigate the specific roles of MC1R and MC3R in experimental atherosclerosis and its associated inflammatory processes.

To address this objective, the contribution of MC1R to the development of atherosclerosis was investigated in apolipoprotein E deficient (Apoe-/- ) mice, a widely used mouse model of atherosclerosis. Apoe-/- mice carrying a mutated and dysfunctional MC1R (Mc1re/e) globally showed accelerated atherosclerosis that was associated with enhanced arterial monocyte accumulation and perturbed cholesterol metabolism. Secondly, the specific contribution of leukocyte MC1R to atherosclerosis was examined via transplantation of Mc1re/e–derived bone marrow into Apoe-/- mice. Leukocyte-specific MC1R deficiency significantly increased total leukocyte counts and particularly CD4+ T cells in the spleen and blood, but it did not affect the development of atherosclerosis or plaque vulnerability. Thirdly, the therapeutic effects of selective activation of MC3R were explored in Apoe-/- mice. Chronic treatment with the potent MC3R agonist [D-Trp8 ]-γ-MSH suppressed systemic inflammation and reduced leukocyte counts in the blood and aorta.

In conclusion, this thesis work advances our understanding of the significant roles of MC1R and MC3R in modulating lipid metabolism, inflammatory responses and leukocyte behavior in the context of experimental atherosclerosis.