Bile Acids Improve Psoriasiform Dermatitis through Inhibition of IL-17A Expression and CCL20-CCR6-Mediated Trafficking of T Cells

J Invest Dermatol. 2022 May;142(5):1381-1390.e11. doi: 10.1016/j.jid.2021.10.027. Epub 2021 Nov 19.

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 T helper 17 cell function, but the underlying mechanism of this action and their therapeutic value in disease models remains unclear. Using an IL-23 minicircle DNA-based murine model of psoriasiform dermatitis, we showed that oral administration of secondary BAs, including lithocholic acid (LCA), deoxycholic acid, and 3-oxoLCA, significantly improved psoriasiform dermatitis without inducing apparent hepatotoxicity. Of the BAs tested, LCA possessed the greatest potency in treating psoriasiform dermatitis. Intravenous administration of LCA at a much lower dosage (compared with oral treatment) showed a comparable antipsoriatic 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 psoriasiform dermatitis with minimal toxicity via direct inhibition of IL-17A production and blockade of CCL20-mediated trafficking, supporting the potential use of BAs in psoriasis.

MeSH terms

  • Animals
  • Bile Acids and Salts / therapeutic use
  • Chemokine CCL20
  • Eczema*
  • Humans
  • Interleukin-17 / metabolism
  • Interleukin-23
  • Mice
  • Psoriasis* / drug therapy
  • Psoriasis* / metabolism
  • Receptors, CCR6

Substances

  • Bile Acids and Salts
  • CCL20 protein, human
  • CCR6 protein, human
  • CCR6 protein, mouse
  • Chemokine CCL20
  • IL17A protein, human
  • Il17a protein, mouse
  • Interleukin-17
  • Interleukin-23
  • Receptors, CCR6