Free Fatty Acid Receptor 4 (FFA4) Activation Ameliorates Imiquimod-Induced Psoriasis in Mice

Abstract

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 CD4+IL-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 TH17 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 TH17 cells may partly contribute to its efficacy. Therefore, we suggest that FFA4 could be a therapeutic target for psoriasis therapy.

Free Fatty Acid 4 Receptor Activation Attenuates Collagen-Induced Arthritis by Rebalancing Th1/Th17 and Treg Cells

“…In previous studies, pro-inflammatory cytokine productions, including Il-17, Tnf-α, Ifn-γ, Il-1β, Il-2, Il-6, Il-23, and Il-27 from immune cells such as T cells, macrophages, dendritic cells, and neutrophils have been shown to be suppressed by n-3 PUFAs [ 38 ]. The involvement of FFA4 in the CpdA-induced suppression of pro-inflammatory cytokines has been shown in allergic asthma ( Il-4 , Il-5 , Il-13 , Ifn-g , and Il-17a ), atopic dermatitis ( Il-4 , Il-13 , Ifn-g , and Il-17a ), and psoriasis ( Il-17a , Il-22 , Il-23 , Il-1b , Ifn-g , and Tnf-a ) models using Ffa4 gene KO mice [ 30 , 39 ]. In the present study, levels of the representative pro-inflammatory Th1/Th17 cytokines ( Il-1b , Tnf-a , Il-6 , and Il-17a ) in a CIA arthritis model were increased by CIA and reversed by CpdA in an Ffa4 gene-dependent manner.…”

“…Endogenous conversion of n-6 to n-3 PUFA in fat-1 transgenic mice restores the balance between Th17 and Treg in CIA [ 16 ]. Previously, we have demonstrated that CpdA activation of Ffa4 suppressed allergic asthma, which is driven by Th2 cytokines, and psoriasis, which is driven by Th17 cells [ 30 , 39 ]. In addition, CpdA treatment suppressed the differentiation of naïve T cells into Th17 cells in vitro and increased the Th17-cell population in a psoriasis-like animal model in an Ffa4 gene-dependent manner [ 39 ].…”

“…Previously, we have demonstrated that CpdA activation of Ffa4 suppressed allergic asthma, which is driven by Th2 cytokines, and psoriasis, which is driven by Th17 cells [ 30 , 39 ]. In addition, CpdA treatment suppressed the differentiation of naïve T cells into Th17 cells in vitro and increased the Th17-cell population in a psoriasis-like animal model in an Ffa4 gene-dependent manner [ 39 ]. Also, CpdA treatment increased the population of Treg cells in an atopic-dermatitis-like animal model in an Ffa4 gene-dependent manner [ 29 ].…”

Role of dietary supplements in the treatment of asthma - a narrative review

“…This leads to attenuation of inflammation, lower mucin secretion, reduction of both pro-inflammatory cytokines (IL-4, IL-5, IL-13, IFN-γ, and IL-17A) and number of immune cells (eosinophils and lymphocytes) in bronchoalveolar lavage fluid. 58 There are reports of omega-3 acids supplementation in mice leading to increased airway reactivity. This phenomenon is a result of interaction with sphingolipid metabolism, and is not associated with inflammation.…”

Metabolic influences on T cell in psoriasis: a literature review

“…In 3D engineered skin models replicating psoriasis conditions, the exogenous introduction of ALA led to reduced T-cell penetration into the epidermal layer, along with a notable reduction in inflammatory markers such as CXCL1, IL-6, and IL-8 ( 42 ). Moreover, the application of a targeted FFA4 agonist resulted in substantial alleviation of IMQ-triggered psoriasis-like skin aberrations and inhibited the transition of CD4+ T cells into Th17 cells ( 43 ).…”