Maresin-1 suppresses imiquimod-induced skin inflammation by regulating IL-23 receptor expression

Natsuko Saito-Sasaki,Emi Mashima,Motonobu Nakamura,Etsuko Okada,Haruna Yoshioka,Shun Ohmori,Takashi Yamaguchi,Yu Sawada,Sanehito Haruyama

doi:10.1038/s41598-018-23623-9

Natsuko Saito-Sasaki, Emi Mashima + Show 7 more

Open Access

https://doi.org/10.1038/s41598-018-23623-9

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Abstract

The anti-inflammatory effect of omega 3 polyunsaturated fatty acids has been confirmed in various inflammatory disease models. Maresin-1 (MaR1) is a lipid mediator derived from the omega-3 fatty acid docosahexaenoic acid (DHA) that has displayed strong anti-inflammatory effects in various inflammatory disease models. However, the effect of topical MaR1 on cutaneous inflammation remains unclear. Therefore, we initially examined the anti-inflammatory effects of topical Maresin-1 using an imiquimod (IMQ)-induced psoriasis-like mouse model of inflammation. Topical MaR1 reduced the ear swelling response as seen in histological findings. RT-PCR and flow cytometry analyses revealed MaR1 had no inhibitory effect on IL-23, but MaR1 suppressed IL-17A production by γδTCRmid+ and CD4+ cells in the skin. These inhibitory effects were also observed in a subcutaneous IL-23-injected psoriasis model. MaR1 downmodulated IL-23 receptor (IL-23R) expression by suppressing retinoic acid-related orphan receptor γt (RORγt) expression and internalization in a clathrin-dependent manner in γδTCRmid+ and CD4+ cells. These results lead to assumptions that topical MaR1 may be a new therapeutic agent for psoriasis and other IL-17-mediated cutaneous inflammatory diseases.

Highlights

Lipid mediators act on various physiological or pathological conditions by regulating lipid metabolism, cell signaling, and inflammation[1,2]
IMQ was applied to ear skin for 5 consecutive days to ensure the effect of Maresin 1 (MaR1) throughout the course of disease, and ear swelling response was measured as an indicator of skin inflammation
These results indicated that MaR1 inhibits IMQinduced psoriasis-like skin inflammation

Summary

Introduction

Lipid mediators act on various physiological or pathological conditions by regulating lipid metabolism, cell signaling, and inflammation[1,2]. DHA treatment suppresses atopic skin inflammation through activation of transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), leading to the conversion of CD4+ T cells to CD4+ FoxP3+ regulatory T cells[4]. These findings suggest that DHA has the potential to suppress various cutaneous inflammatory conditions. Among the specialized pro-resolving lipid mediators (SPMs), Maresin 1 (MaR1) has inhibitory effects on experimental inflammatory disease models[8,9] MaR1 consistently protects mice against experimental colitis by inhibiting the NF-κB pathway, and inflammatory cytokines[8]. MaR1 resolves IL-17A production via downmodulating IL-23R expression on γδT cells and CD4+ T cells in the skin

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