Targeting the melanocortin receptor system to reduce leukocyte recruitment following stroke

Abstract

Leukocyte recruitment has been shown to contribute to a destructive inflammatory response following stroke which exacerbates injury. The melanocortin receptor system (MRS) has been shown to reduce leukocyte recruitment in a number of disease models however the relative contribution of the receptors that mediate these effects (MC1, MC3 and MC4) have yet to be determined. This study aims to evaluate the anti‐inflammatory potential of the MRS in stroke.In a murine model of global stroke, intravital microscopy revealed significant recruitment of leukocytes within 40 minutes of reperfusion. This leukocyte recruitment was found to be enhanced in MC1 mutant (recessive yellow) mice but not in MC3 null. In WT mice Treatment with the pan receptor agonist α‐MSH reduced leukocyte recruitment. However antagonism of MC3 and MC4 failed to abrogate the anti‐inflammatory effects of α‐MSH by 40 minutes of reperfusion, but was able to blunt these effects at 2h. In vitro experiments using human cells in a flow chamber leukocyte recruitment model, confirmed α‐MSH to reduce leukocyte endothelial interactions in human cells and was found to act upon neutrophils but not the endothelium.These results suggest an important role of MC1 in reducing leukocyte recruitment early in reperfusion following stroke. However as the inflammatory reaction progresses the role of other MCs may become more prominent.Funded by the British Heart Foundation