Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Korea.
Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
Int J Mol Sci. 2022 Apr 19;23(9):4482. doi: 10.3390/ijms23094482.
Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) has been used as an adjunct therapy for psoriasis due to its anti-inflammatory properties. Free fatty acid receptor 4 (FFA4 or GPR120) is a receptor-sensing n-3 PUFA. In the present study, we examined whether FFA4 acted as a therapeutic target for n-3 PUFA in psoriasis therapy. Experimentally, psoriasis-like skin lesions were induced by treatment with imiquimod for 6 consecutive days. A selective FFA4 agonist, Compound A (30 mg/kg), was used in FFA4 WT and FFA4 KO mice. Imiquimod-induced psoriasis-like skin lesions, which present as erythematous papules and plaques with silver scaling, as well as markedly elevated IL-17/IL-23 cytokine levels in skin tissues, were significantly suppressed by Compound A in FFA4 WT mice, but not in FFA4 KO mice. Enlarged lymph nodes and spleens, as well as imiquimod-induced, elevated IL-17/IL-23 cytokine levels, were also strongly suppressed by Compound A in FFA4 WT mice, but not in FFA4 KO mice. Imiquimod-induced increases in the CD4IL-17A T cell population in lymph nodes and spleens were suppressed by Compound A treatment in FFA4 WT mice; however, this was not seen in FFA4 KO mice. Furthermore, compound A suppressed the differentiation of CD4 naïve T cells from splenocytes into T17 cells in an FFA4-dependent manner. In conclusion, we demonstrated that the activation of FFA4 ameliorates imiquimod-induced psoriasis, and the suppression of the differentiation of T17 cells may partly contribute to its efficacy. Therefore, we suggest that FFA4 could be a therapeutic target for psoriasis therapy.
膳食补充 n-3 多不饱和脂肪酸（n-3 PUFA）因其具有抗炎特性，已被用作银屑病的辅助治疗方法。游离脂肪酸受体 4（FFA4 或 GPR120）是一种感知 n-3 PUFA 的受体。在本研究中，我们研究了 FFA4 是否作为 n-3 PUFA 在银屑病治疗中的治疗靶点。实验上，通过连续 6 天给予咪喹莫特处理诱导银屑病样皮肤损伤。在 FFA4 WT 和 FFA4 KO 小鼠中使用了选择性 FFA4 激动剂化合物 A（30mg/kg）。在 FFA4 WT 小鼠中，化合物 A 显著抑制咪喹莫特诱导的银屑病样皮肤损伤，其表现为红斑丘疹和银鳞斑块，以及皮肤组织中显著升高的 IL-17/IL-23 细胞因子水平，但在 FFA4 KO 小鼠中则没有。在 FFA4 WT 小鼠中，化合物 A 还强烈抑制了增大的淋巴结和脾脏，以及咪喹莫特诱导的、升高的 IL-17/IL-23 细胞因子水平，但在 FFA4 KO 小鼠中则没有。在 FFA4 WT 小鼠中，化合物 A 抑制了淋巴结和脾脏中 CD4IL-17A T 细胞群体因咪喹莫特诱导而增加；然而，在 FFA4 KO 小鼠中则没有观察到这种情况。此外，化合物 A 以 FFA4 依赖的方式抑制了来自脾细胞的 CD4 初始 T 细胞向 T17 细胞的分化。总之，我们证明了 FFA4 的激活改善了咪喹莫特诱导的银屑病，并且 T17 细胞的分化抑制可能部分有助于其疗效。因此，我们认为 FFA4 可能是银屑病治疗的治疗靶点。
