Melanocortin 3 receptor activation with [D-Trp8]-γ-MSH suppresses inflammation in apolipoprotein E deficient mice

James J Kadiri,Keshav Thapa,Katja Kaipio,Minying Cai,Victor J Hruby,Petteri Rinne

doi:10.1016/j.ejphar.2020.173186

Abstract

The melanocortin MC1 and MC3 receptors elicit anti-inflammatory actions in leukocytes and activation of these receptors has been shown to alleviate arterial inflammation in experimental atherosclerosis. Thus, we aimed to investigate whether selective targeting of melanocortin MC3 receptor protects against atherosclerosis. Apolipoprotein E deficient (ApoE−/−) mice were fed high-fat diet for 12 weeks and randomly assigned to receive either vehicle (n = 11) or the selective melanocortin MC3 receptor agonist [D-Trp(8)]-gamma-melanocyte-stimulating hormone ([D-Trp8]-γ-MSH; 15 μg/day, n = 10) for the last 4 weeks. Lesion size as well as macrophage and collagen content in the aortic root plaques were determined. Furthermore, leukocyte counts in the blood and aorta and cytokine mRNA expression levels in the spleen, liver and aorta were quantified. No effect was observed in the body weight development or plasma cholesterol level between the two treatment groups. However, [D-Trp8]-γ-MSH treatment significantly reduced plasma levels of chemokine (C–C motif) ligands 2, 4 and 5. Likewise, cytokine and adhesion molecule expression levels were reduced in the spleen and liver of γ-MSH-treated mice, but not substantially in the aorta. In line with these findings, [D-Trp8]-γ-MSH treatment reduced leukocyte counts in the blood and aorta. Despite reduced inflammation, [D-Trp8]-γ-MSH did not change lesion size, macrophage content or collagen deposition of aortic root plaques. In conclusion, the findings indicate that selective activation of melanocortin MC3 receptor by [D-Trp8]-γ-MSH suppresses systemic and local inflammation and thereby also limits leukocyte accumulation in the aorta. However, the treatment was ineffective in reducing atherosclerotic plaque size.

Highlights

The melanocortins consist of α, β- and γ-melanocyte-stimulating hormones and adrenocorticotropic hormone
Melanocortin MC2 and MC3 receptors are unique in this regard because the former can only be activated by adrenocorticotropic hormone, while γ-melanocyte-stimulating hormone (γ-MSH) is the only endogenous peptide known to have a high affinity for melanocortin MC3 receptor (Brzoska et al, 2008; Catania et al, 2004)
Using immunohistochemistry, we found that aortic root sections from HFDfed ApoE−/− mice show subtle but clear expression of melanocortin MC3 receptor, which localized in the luminal side of atherosclerotic plaques (Fig. 1A)

Summary

Introduction

The melanocortins consist of α-, β- and γ-melanocyte-stimulating hormones and adrenocorticotropic hormone. Melanocortin MC2 and MC3 receptors are unique in this regard because the former can only be activated by adrenocorticotropic hormone, while γ-melanocyte-stimulating hormone (γ-MSH) is the only endogenous peptide known to have a high affinity for melanocortin MC3 receptor (Brzoska et al, 2008; Catania et al, 2004). The anti-inflammatory actions of melanocortins are mainly attributable to melanocortin MC1 and MC3 receptors, which are widely expressed in the cells of the immune system. Activation of these receptors has shown to provide protection against multiple inflammatory disorders such as rheumatoid arthritis and colitis (Catania et al, 2010). We and others have reported that activating these receptors alleviates inflammation in the vasculature (Catania et al, 2004; Getting et al, 1999b; Ichiyama et al, 1999; Manna and Aggarwal, 1998; Rinne et al, 2017, 2014)

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