954 Maresin-1 inhibits IL-23 receptors via down-regulation of RORt expression and internalization in an imiquimod-induced psoriasis model mouse

Abstract

The anti-inflammatory effect of ω3 polyunsaturated fatty acid has been confirmed in various inflammatory disease models. Maresin-1 (MaR1) is derived from ω3 fatty acid, docosahexaenoic acid (DHA), and has strong anti-inflammatory effects on various inflammatory disease models. The aim of this study was to elucidate the effect of MaR1 on cutaneous inflammation, which had been unclear. In an imiquimod（IMQ）-induced psoriasis model mouse, the MaR1 reduced ear swelling response via suppression of IL-17A expression. Although MaR1 had no inhibitory effect on IL-23, MaR1 suppressed IL-17A production. MaR1 down-modulated IL-23 receptors (IL-23R) expression through inhibition of retinoic acid related orphan receptor γt (RORγt) expression. Furthermore, we discovered that MaR-1 also down-regulates the effect of IL-23 via internalization of IL-23R in γδTCR mid+ and CD4+ cells. At present, two distinct receptor internalization mechanisms are known. One pathway via clathrin-coated pits and the other via caveolae. To clarify which mechanism is related to MaR1-mediated IL-23R internalization, we examined the effects of nystatin, which disrupts internalization via caveolae, and chlorpromazine and clathrin specific inhibitor (Pitstop 2), both of which disrupt internalization via clathrin-coated pits. A MaR-1 induced internalization was significantly inhibited both by chlorpromazine and Pitstop 2, whereas it was completely unaffected by nystatin. These results lead to assumptions that MaR1 would be new a therapeutic candidate for psoriasis and other IL-17-mediated cutaneous inflammatory diseases.