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Melanocortin 3 receptors control crystal-induced inflammation

Stephen J. Getting^*, Connie W. Lam^*, Airu S. Chen, Paolo Grieco and Mauro Perretti^*,1

^* The William Harvey Research Institute, London, UK;

Merck Research Laboratories, Rahway, New Jersey, USA; and

Department of Pharmaceutical Chemistry and Toxicology, Universitá di Napoli, Naples, Italy

¹Correspondence: The William Harvey Research Institute, Queen Mary School of Medicine and Dentistry, Charterhouse Sq., London EC1M 6BQ, UK. E-mail: m.perretti{at}qmul.ac.uk

In this study we have characterized the anti-inflammatory profile of a selective melanocortin type 3 receptor (MC3-R) ligand [D-Trp⁸]--MSH, validating in vitro results with analyses in mice deficient for this receptor subtype. In wild-type (WT) macrophages, [D-Trp⁸]--MSH activated MC3-R (as tested by accumulation of cyclic AMP) and inhibited (50%) the release of interleukin (IL)-1 and the chemokine KC (CXCL1), but was ineffective in cells taken from MC3-R null mice. In vivo, administration of 3–30 µg [D-Trp⁸]--MSH significantly inhibited leukocyte influx and cytokine production in a model of crystal-induced peritonitis, and these effects were absent in MC3-R null mice or blocked by coadministration of an MC3-R antagonist. Finally, in a model of gouty arthritis, direct injection of urate crystals into the rat joint provoked a marked inflammatory reaction that was significantly inhibited (70%) by systemic or local administration of [D-Trp⁸]--MSH. In conclusion, using an integrated transgenic and pharmacological approach, we provide strong proof of concept for the development of selective MC3-R agonists as novel anti-inflammatory therapeutics.—Getting, S. J., Lam, C. W., Chen, A. S., Grieco, P., Perretti, M. Melanocortin 3 receptors control crystal-induced inflammation.

Key Words: neutrophil trafficking • macrophage activation • anti-inflammation • drug discovery

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