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Melanocortin receptor 1 (MC1-R) is expressed in leukocytes, where it mediates anti-inflammatory actions. We have previously observed that global deficiency of MC1-R signaling perturbs cholesterol homeostasis, increases arterial leukocyte accumulation and accelerates atherosclerosis in apolipoprotein E knockout (Apoe-/-) mice. Since various cell types besides leukocytes express MC1-R, we aimed at investigating the specific contribution of leukocyte MC1-R to the development of atherosclerosis. For this purpose, male Apoe-/- mice were irradiated, received bone marrow from either female Apoe-/- mice or MC1-R deficient Apoe-/- mice (Apoe-/- Mc1re/e) and were analyzed for tissue leukocyte profiles and atherosclerotic plaque phenotype. Hematopoietic MC1-R deficiency significantly elevated total leukocyte counts in the blood, bone marrow and spleen, an effect that was amplified by feeding mice a cholesterol-rich diet. The increased leukocyte counts were largely attributable to expanded lymphocyte populations, particularly CD4+ T cells. Furthermore, the number of monocytes was elevated in Apoe-/- Mc1re/e chimeric mice and it paralleled an increase in hematopoietic stem cell count in the bone marrow. Despite robust leukocytosis, atherosclerotic plaque size and composition as well as arterial leukocyte counts were unaffected by MC1-R deficiency. To address this discrepancy, we performed an in vivo homing assay and found that MC1-R deficient CD4+ T cells and monocytes were preferentially entering the spleen rather than homing in peri-aortic lymph nodes. This was mechanistically associated with compromised chemokine receptor 5 (CCR5)-dependent migration of CD4+ T cells and a defect in the recycling capacity of CCR5. Finally, our data demonstrate for the first time that CD4+ T cells also express MC1-R. In conclusion, MC1-R regulates hematopoietic stem cell proliferation and tissue leukocyte counts but its deficiency in leukocytes impairs cell migration via a CCR5-dependent mechanism.

Backgroundα-Melanocyte-stimulating hormone (α-MSH) regulates diverse physiological functions by activating melanocortin receptors (MC-R). α-MSH is predominantly expressed in the pituitary gland, but it is also found in several peripheral tissues such as the skin and heart. However, the role of α-MSH and its possible target receptors in the heart remain completely unknown. Therefore, we sought to investigate whether α-MSH could be involved in the regulation of pathological cardiac remodeling.MethodsTissue α-MSH concentrations and the effects of chronic α-MSH administration were investigated in mice subjected to transverse aortic constriction (TAC). Rat H9c2 cells, neonatal mouse ventricular myocytes and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) were used to study the effects of α-MSH and selective MC-R agonists. Inducible cardiomyocyte-specific melanocortin 5 receptor (MC5-R) knockout mouse model was engineered to investigate the role of MC5-R in cardiac hypertrophy.Resultsα-MSH was highly expressed in the mouse heart, particularly in the ventricles, and its level was reduced in the left ventricles of TAC-operated mice. Administration of a stable α-MSH analogue protected mice against TAC-induced cardiac hypertrophy and systolic dysfunction.In vitroexperiments revealed that cardiomyocytes serve as effector cells for the α-MSH mediated antihypertrophic signaling and that selective activation of MC5-R mimics the actions of α-MSH. In keeping with these findings, MC5-R was downregulated in the failing mouse heart and stressed hiPSC-CMs. Silencing of MC5-R in mouse cardiomyocytes induced hypertrophy and fibrosis markersin vitroand aggravated TAC-induced cardiac hypertrophy and fibrosisin vivo. Conversely, pharmacological activation of MC5-R improved systolic function and reduced cardiac fibrosis in TAC-operated mice.Conclusionsα-MSH is expressed in the heart and protects against pathological cardiac remodeling by activating MC5-R in cardiomyocytes. These results suggest that analogues of naturally occurring α-MSH, that have been recently approved for clinical use and have agonistic activity at MC5-R, may be of benefit in treating heart failure.