Substantial evidence now signifies that resolution of inflammation is a highly coordinated, active process dictated by the spatial-temporal generation of pro-resolving mediators that act on specific receptors to modulate cell and tissue reactivity. Thus, in contrast to current anti-inflammatories that typically target the ‘heating-up’ period of the immune response, new therapeutics based on pro-resolution mediators would accelerate the way our body naturally regulates an inflammatory reaction, prompting the regain of physiological tissue function.
Melanocortins are a group of endogenous pro-resolving mediators; these include α- and γ-melanocyte-stimulating hormone (MSH) and adrenocorticotrophin (ACTH). These polypeptides block neutrophilic infiltration and the production of pro-inflammatory cytokines from target cells, yet also activate pro-resolving processes including the induction of heme oxygenase 1 via signaling through specific melanocortin (MC) receptors. Definition of the receptors regulating melanocortin anto-arthritic effects can guide innovative drug discovery programmes.
We have observed high and relatively stable expression of melanocortin receptor type 1 (MC1) in macrophages, synovial tissue and sub-endothelial tissue in the mesenteric vasculature, with little expression of the MC3 receptor. However, upon application of an insult such as an ischemia-reperfusion procedure or induction of joint arthritis, marked upregulation of MC3 gene product occurred, with MC1 remaining stable. We postulate that in these settings MC3 mRNA is over-expressed in the affected tissue not only in view of the marked influx of myeloid cells, but also through genuine gene promoter activation, and that this is part of a homeostatic process aiming at directing the host response through resolution pathways. On going work in the synovia of patients suffering from Rheumatoid Arthritis will indicate the relevance of MC1 and MC3 expression to man.
I acknowledge the contribution of my colleagues Prof C Pitzalis, Drs M Bombardieri, T Montero-Melendez and HB Patel. Our work on Melanocortin receptors is funded by The British Heart Foundation (PG/11/48/28981) and the Medical Research Council (MR/K013068/1).
Disclosure of Interest M. Perretti Grant/research support from: Action Pharma AS; SynactPharma ApS