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

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.

Long Chain Fatty Acids as Modulators of Immune Cells Function: Contribution of FFA1 and FFA4 Receptors

“…In HFD-fed obese mice, the compound improved glucose tolerance and insulin sensitivity and decreased hyperinsulinemia and hepatic steatosis (Oh et al, 2014 ). Compound A reduced 2,4-dinitrochlorobenzene-induced atopic dermatitis that is mediated through FFA4 receptor activation and Foxp3+ Treg increase in mice (Son et al, 2020 ). However, other studies have suggested that therapies based only on FFA4 receptor activation would not be helpful in the treatment of inflammatory diseases.…”

Therapy and mechanism of natural polysaccharides for atopic dermatitis treatment

“…Mice lacking Tregs eventually develop autoimmune diseases and allergic symptoms, which indicates that Tregs are necessary for the maintenance of self-tolerance [147][148]. Tregs can prevent the polarisation of Th2 cells by secreting inhibitory cytokines including IL-10, IL-35, and TNF-β, while AD is generally considered a Th2-driven disease [149] Natural polysaccharides have a function of immunostimulating effects and can increase the proportion of Tregs [150]. Polysaccharides from Angelica gigas Nakai (ISAg) induced the polarization of CD4 + T cells toward the acquisition of the Th1 phenotype and the expansion of Treg in Yet40 B6 mice, which suggests that ISAg may be effective for AD therapy [88].…”

Development of Free Fatty Acid Receptor 4 (FFA4/GPR120) Agonists in Health Science

“…Administration of compound improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity, and decreased hepatic steatosis in obese mice fed a high-fat diet ( Oh et al ., 2014 ). Recently, compound A was used to verify that beneficial effects of DHA on atopic dermatitis is mediated through FFA4 activation and Foxp3 + Treg increase in combination with FFA4 KO mice ( Son et al ., 2020 ).…”