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Free fatty acid receptor 4 (FFA4) activation ameliorates 2,4-dinitrochlorobenzene-induced atopic dermatitis by increasing regulatory T cells in mice

Authors: So-Eun Son1, Soo-Jin Park1, Jung-Min Koh2, Dong-Soon Im1,3
1 College of Pharmacy, Pusan National University, Busan 46241, Republic of Korea
2 Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
3 Laboratory of Pharmacology, College of Pharmacy, and Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
Correspondence to: Dong-Soon Im: imds@khu.ac.kr,
DOI: 10.1038/s41401-020-0435-1
Received: 20 February 2020
Accepted: 9 May 2020
Advance online: 18 June 2020

Abstract

High dose intake of docosahexaenoic acid showed beneficial effects on atopic dermatitis in patients and was found to increase regulatory T cells in mice, but its molecular target has not been identified. Free fatty acid receptor 4 (FFA4, also known as GPR120) is a receptor sensing polyunsaturated long-chain fatty acids including docosahexaenoic acid. In the present study, we examined whether FFA4 acted as a therapeutic target of docosahexaenoic acid for treating atopic dermatitis. Experimental atopic dermatitis was induced in mice by 2,4-dinitrochlorobenzene (DNCB) sensitization on day 0, followed by repeated DNCB challenges from D7 to D48. The mice were treated with a selective agonist compound A (30 mg· kg−1· d−1, ip) from D19 to D48, and sacrificed on D49. We found that DNCB-induced atopic dermatitis-like skin lesions, i.e. hypertrophy and mast cell infiltration in skin tissues, as well as markedly elevated serum IgE levels. Administration of compound A significantly suppressed the atopic responses in ears and lymph nodes, such as hypertrophy and mast cell infiltration in the ears, enlarged sizes of lymph nodes, and elevated serum IgE and levels of cytokines IL-4, IL-13, IL-17, and IFN-γ in ear tissue. The therapeutic effects of compound A were abolished by FFA4 knockout. Similarly, increased CD4+Foxp3+ regulatory T-cell population in lymph nodes was observed in wide-type mice treated with compound A, but not seen in FFA4-deficient mice. In conclusion, we demonstrate that activation of FFA4 ameliorates atopic dermatitis by increasing CD4+Foxp3+ regulatory T cells, suggesting FFA4 as a therapeutic target for atopic dermatitis.
Keywords: atopic dermatitis; 2 4-dinitrochlorobenzene; free fatty acid receptor 4; FFA4 agonist; polyunsaturated fatty acids; Omega-3; Treg cells; skin

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