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Bile acids improve psoriasiform dermatitis through inhibition of IL-17A expression and CCL20-CCR6 mediated trafficking of T cells

Published:November 19, 2021DOI:https://doi.org/10.1016/j.jid.2021.10.027

      ABSTRACT

      Bile acids (BAs), produced in the liver and further transformed in the gut, are cholesterol-derived molecules involved in essential physiological processes. Recent studies suggest that BAs regulate Th17 cell function, but the underlying mechanism of this action and their therapeutic value in disease models remains unclear. Using an IL-23 minicircle DNA (MC) based murine model of psoriasiform dermatitis (PsD), we showed that oral administration of secondary BAs, including lithocholic acid (LCA), deoxycholic acid (DCA) and 3-oxoLCA, significantly improved PsD without inducing apparent hepatotoxicity. Of the BAs tested, LCA possessed the greatest potency in treating PsD. Intravenous administration of LCA at a much lower dosage (compared to oral treatment) showed a comparable anti-psoriatic effect and markedly suppressed the IL-17A response. Ex vivo experiments revealed that LCA reduced IL-17A production in IL-23-stimulated murine T cells in the absence of BA receptors TGR5 or FXR. Strikingly, BAs inhibited CCL20 expression in keratinocytes, which led to reduced migration of CCR6-expressing Jurkat cells cultured in the conditioned medium of stimulated keratinocytes. Thus, BAs improve PsD with minimal toxicity via direct inhibition of IL-17A production and blockade of CCL20-mediated trafficking, supporting the potential use of BAs in psoriasis.

      Keywords

      Abbreviations:

      BAs (Bile acids), CCL20 (C-C motif chemokine ligand 20), cLNs (cervical lymph nodes), DCA (deoxycholic acid), FXR (farnesoid-X-receptor), IHC (Immunohistochemistry), IL (interleukin), H&E (hematoxylin and eosin), LCA (lithocholic acid), MC (minicircle DNA), PsD (psoriasiform dermatitis), RORγt (RAR-related orphan receptor γt), γδ T cell (Gamma-delta T cell), γδ-low (TCR γδ-low expressing), TGR5 (G-protein-coupled bile acid receptor), Th (T helper), TNF-α (tumor necrosis factor-α), Tregs (regulatory T cells)
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