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Arterioscler Thromb Vasc Biol. 2015 Sep;35(9):1936-44. doi: 10.1161/ATVBAHA.115.305348. Epub 2015 Jun 25.

Both MC1 and MC3 Receptors Provide Protection From Cerebral Ischemia-Reperfusion-Induced Neutrophil Recruitment.

Author information

1
From the Division of Brain Sciences, Imperial College London, London, United Kingdom (P.M.H., P.F.D., F.N.E.G.); LSU Shreveport, LA (M.T., U.C.); William Harvey Research Institute, Barts and The Royal London School of Medicine, London, United Kingdom (D.C., M.P.); Faculty of Science and Technology, University of Westminster, London, United Kingdom (S.J.G.); and LSU Health Science Center, Shreveport, LA (P.M.H., A.W.O., F.N.E.G.).
2
From the Division of Brain Sciences, Imperial College London, London, United Kingdom (P.M.H., P.F.D., F.N.E.G.); LSU Shreveport, LA (M.T., U.C.); William Harvey Research Institute, Barts and The Royal London School of Medicine, London, United Kingdom (D.C., M.P.); Faculty of Science and Technology, University of Westminster, London, United Kingdom (S.J.G.); and LSU Health Science Center, Shreveport, LA (P.M.H., A.W.O., F.N.E.G.). fgavin@lsuhsc.edu.

Abstract

OBJECTIVE:

Neutrophil recruitment is a key process in the pathogenesis of stroke, and may provide a valuable therapeutic target. Targeting the melanocortin (MC) receptors has previously shown to inhibit leukocyte recruitment in peripheral inflammation, however, it is not known whether treatments are effective in the unique cerebral microvascular environment. Here, we provide novel research highlighting the effects of the MC peptides on cerebral neutrophil recruitment, demonstrating important yet discrete roles for both MC1 and MC3.

APPROACH AND RESULTS:

Using intravital microscopy, in 2 distinct murine models of cerebral ischemia-reperfusion (I/R) injury, we have investigated MC control for neutrophil recruitment. After global I/R, pharmacological treatments suppressed pathological neutrophil recruitment. MC1 selective treatment rapidly inhibited neutrophil recruitment while a nonselective MC agonist provided protection even when coadministered with an MC3/4 antagonist, suggesting the importance of early MC1 signaling. However, by 2-hour reperfusion, MC1-mediated effects were reduced, and MC3 anti-inflammatory circuits predominated. Mice bearing a nonfunctional MC1 displayed a transient exacerbation of neutrophil recruitment after global I/R, which diminished by 2 hours. However importantly, enhanced inflammatory responses in both MC1 mutant and MC3 (-/-) mice resulted in increased infarct size and poor functional outcome after focal I/R. Furthermore, we used an in vitro model of leukocyte recruitment to demonstrate these anti-inflammatory actions are also effective in human cells.

CONCLUSIONS:

These studies reveal for the first time MC control for neutrophil recruitment in the unique pathophysiological context of cerebral I/R, while also demonstrating the potential therapeutic value of targeting multiple MCs in developing effective therapeutics.

KEYWORDS:

inflammation; leukocyte; melanocortins; neutrophil; stroke

PMID:
26112010
PMCID:
PMC4552587
DOI:
10.1161/ATVBAHA.115.305348
[Indexed for MEDLINE]
Free PMC Article

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