{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T21:35:04Z","timestamp":1791668104778,"version":"4.3.4"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T00:00:00Z","timestamp":1669248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Melanocortins are peptides endowed with anti-inflammatory and pro-resolving activities. Many of these effects are mediated by the Melanocortin receptor 1 (MC<jats:sub>1<\/jats:sub>) as reported in several experimental settings. As such, MC<jats:sub>1<\/jats:sub> can be a viable target for the development of new therapies that mimic endogenous pro-resolving mediators. The aim of this study was to assess the immunopharmacology of a selective MC<jats:sub>1<\/jats:sub> agonist (PL8177) <jats:italic>in vitro<\/jats:italic> and in a mouse model of inflammatory arthritis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>PL8177 and the natural agonist \u03b1MSH were tested for activation of mouse and human Melanocortin receptors (MC<jats:sub>1,3,4,5<\/jats:sub>), monitoring cAMP accumulation and ERK1\/2 phosphorylation, using transiently transfected HEK293A cells. The anti-inflammatory and pro-resolving effects of PL8177 and \u03b1MSH were evaluated using mouse peritoneal Macrophages. Finally, a model of K\/BxN serum transfer induced arthritis was used to determine the <jats:italic>in vivo<\/jats:italic> potential of PL8177.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>PL8177 activates mouse and human MC<jats:sub>1<\/jats:sub> with apparent EC<jats:sub>50<\/jats:sub> values of 0.01 and 1.49 nM, respectively, using the cAMP accumulation assay. Similar profiles were observed for the induction of ERK phosphorylation (EC<jats:sub>50<\/jats:sub>: 0.05 and 1.39 nM). PL8177 displays pro-resolving activity (enhanced Macrophage efferocytosis) and counteracts the inflammatory profile of zymosan-stimulated macrophages, reducing the release of IL-1\u03b2, IL-6, TNF-\u03b1 and CCL-2. In the context of joint inflammation, PL8177 (3mg\/kg i.p.) reduces clinical score, paw swelling and incidence of severe disease as well as the recruitment of immune cells into the arthritic joint.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results demonstrate that the MC<jats:sub>1<\/jats:sub> agonism with PL8177 affords therapeutic effects in inflammatory conditions including arthritis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Significance<\/jats:title><jats:p>Drugs targeting the Melanocortin system have emerged as promising therapeutics for several conditions including inflammation or obesity. Multiple candidates are under clinical development, and some have already reached approval. Here we present the characterization of a novel drug candidate, PL8177, selective for the Melanocortin 1 receptor (MC<jats:sub>1<\/jats:sub>), demonstrating its selectivity profile on cAMP and ERK1\/2 phosphorylation signaling pathways, of relevance as selective drugs will translate into lesser off-target effect. PL8177 also demonstrated, not only anti-inflammatory activity, but pro-resolving actions due to its ability to enhance efferocytosis (i.e. the phagocytosis of apoptotic cells), endowing this molecule with therapeutic advantages compared to classical anti-inflammatory drugs. Using a mouse model of inflammatory arthritis, the compound demonstrated <jats:italic>in vivo<\/jats:italic> efficacy by reducing clinical score, paw swelling and overall disease severity. Taken together, these results present Melanocortin-based therapies, and specifically targeting MC<jats:sub>1<\/jats:sub> receptor, as a promising strategy to manage chronic inflammatory diseases.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.1078678","type":"journal-article","created":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T11:33:10Z","timestamp":1669289590000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Pro-resolving and anti-arthritic properties of the MC1 selective agonist PL8177"],"prefix":"10.3389","volume":"13","author":[{"given":"Jose","family":"Garrido-Mesa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethan 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