The resolution of inflammation is now known to be an active process, armed with a multitude of mediators both lipid and protein in nature. Melanocortins are peptides endowed with considerable promise with their proresolution and anti-inflammatory effects in preclinical models of inflammatory disease, with tissue protective effects. These peptides and their targets are appealing because they can be seen as a natural way of inducing these effects as they harness endogenous pathways of control. Whereas most of the information generated about these mediators derives from several acute models of inflammation (such as zymosan induced peritonitis), there is some indication that these mediators may inhibit chronic inflammation by modulating cytokines, chemokines, and leukocyte apoptosis. In addition, proresolving mediators and their mimics have often been tested alongside therapeutic protocols, hence have been tested in settings more relevant to real life clinical scenarios. We provide here an overview on some of these mediators with a focus on melanocortin peptides and receptors, proposing that they may unveil new opportunities for innovative treatments of inflammatory arthritis. 1. Inflammation: Onset and Resolution One novel approach to the area of inflammation, developed over the last twenty years, is the concept of resolution of inflammation. Current therapies suppress active processes of inflammation, for example, NSAIDs (nonsteroidal anti-inflammatory drugs) block cyclo-oxygenases, glucocorticoids inhibit generation of multiple cytokines, and biologics such as anti-TNFα and anti-CD20 therapies, target specific effectors or antigens. However, this may be only half the story. The story of inflammation begins with a tissue insult originating from an infection, trauma, or damage. The affected tissue secretes signals including autacoids, plasma-derived mediators such as kinins and complement factors, culminating with the now prominent cytokines and chemokines. There are multiple molecules that constitute a distress signal. This leads to an initial recruitment of neutrophils, (or eosinophils, upon parasite attack) which mop up any initial infection and call in macrophages, which are also inflammatory. Once neutrophils and macrophages have cleared the inflammation, the neutrophils undergo apoptosis, the macrophage changes its phenotype into a proresolving and tissue repair one, and then leaves and the tissue should return to its baseline uninflamed state [1]. However this return to baseline is not, as was once thought, characterised solely by absence of the
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