The Melanocortin Agonist AP214 Exerts Anti-Inflammatory and Proresolving Properties

Abstract

Synthetic and natural melanocortin (MC) peptides afford inhibitory properties in inflammation and tissue injury, but characterization of receptor involvement is still elusive. We used the agonist AP214 to test MC-dependent anti-inflammatory effects. In zymosan peritonitis, treatment of mice with AP214 (400 to 800 g/kg) inhibited cell infiltration, an effect retained in MC receptor type 1, or MC 1 , mutant mice but lost in MC 3 null mice. In vitro, cytokine release from zymosan-stimulated macrophages was affected by AP214, with approximately 80%, 30%, and 40% reduction in IL-1␤, tumor necrosis factor-␣, and IL-6, respectively. Inhibition of IL-1␤ release was retained in MC 1 mutant cells but was lost in MC 3 null cells. Furthermore, AP214 augmented uptake of zymosan particles and human apoptotic neutrophils by wild-type macrophages: this proresolving property was lost in MC 3 null macrophages. AP214 displayed its pro-efferocytotic effect also in vivo.

Pharmacological Activation of the Melanocortin System Limits Plaque Inflammation and Ameliorates Vascular Dysfunction in Atherosclerotic Mice

“…These findings are supported by other studies proving that pharmacological targeting of MC-Rs suppresses the secretion of proinflammatory mediators by macrophages and induces M2 polarization in experimental models of inflammatory disease. 10,32,33 Consistent with the finding of decreased 18 F-FDG signal and altered macrophage phenotype, we demonstrate that the systemic inflammation profile was favorably modified in MT-II-treated mice. Specifically, MT-II treatment was able suppress the plasma levels of interleukin-1β and interleukin-6, which are considered as proinflammatory mediators promoting atherosclerosis.…”

“…Specifically, MT-II treatment was able suppress the plasma levels of interleukin-1β and interleukin-6, which are considered as proinflammatory mediators promoting atherosclerosis. [34][35][36] Recent research by others, demonstrating anti-inflammatory potential of melanocortin peptides, 4,10,11 corroborates our findings and a suggestion that melanocortin activation could also attenuate the chronic inflammation associated with atherosclerosis. Using a variety of approaches from acute in vitro models to chronic administration under in vivo settings, α-MSH and synthetic MC-R agonists have been shown to reduce cytokine release by macrophages, with a preferential effect on interleukin-6 release, and to inhibit leukocyte trafficking in the inflamed vasculature.…”

“…Using a variety of approaches from acute in vitro models to chronic administration under in vivo settings, α-MSH and synthetic MC-R agonists have been shown to reduce cytokine release by macrophages, with a preferential effect on interleukin-6 release, and to inhibit leukocyte trafficking in the inflamed vasculature. 10,11 These anti-inflammatory actions are strongly linked to MC1-R and MC3-R signaling and the ability of these receptors to inhibit the activation of the nuclear transcription factor nuclear factor-κB, 3,37,38 which governs the expression of numerous cytokines, cytokine receptors, chemokines, and adhesion molecules. Furthermore, the expression of MC1-R and MC3-R is widespread in the cells of the immune system, including macrophages, B and T lymphocytes, dendritic cells, and endothelial cells.…”

“…8,9 Conversely, selective MC1-R and MC3-R agonists exert anti-inflammatory actions and put in motion proresolving processes. [10][11][12][13] Recent data also indicate that MC1-R activation in an inflamed vasculature can inhibit cell adhesion and migration by acting on the adherent leukocytes and reduce the levels of a variety of chemokines, which are known to contribute to the pathogenesis of atherosclerosis. However, these findings have been exclusively derived from acute experiments such as vascular and cardiac ischemia/reperfusion models, whereas the potential of MC1-R and MC3-R activation in chronic inflammatory conditions such as atherosclerosis remains unexplored.…”

Melanocortin peptides protect chondrocytes from mechanically induced cartilage injury

“…They reduce the host's inflammatory response by modulating the production of pro-inflammatory mediators [59,63,64], and maybe even more importantly, by actively stimulating the resolution phase of inflammation through inducing IL-10 and heme oxygenase-1, which possess powerful anti-inflammatory and pro-resolving properties [83,84]. Protective effects have been demonstrated extensively in murine models of gout [59][60][61] and RA [62].…”