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.
Zhenrui Shi  1 ,  Xuesong Wu  2 ,  Chun-Yi Wu  3 ,  Satya P Singh  4 ,  Timothy Law  2 ,  Daisuke Yamada  2 ,  Mindy Huynh  2 ,  William Liakos  2 ,  Guiyan Yang  5 ,  Joshua M Farber  4 ,  Yu-Jui Yvonne Wan  5 ,  Samuel T Hwang  6
Affiliations
  • 1. Department of Dermatology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, California, USA.
  • 2. Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, California, USA.
  • 3. Department of Neurology, School of Medicine, University of California, Davis, Sacramento, California, USA; UC Davis Bioanalysis and Pharmacokinetics Core facility, Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, California, USA.
  • 4. Inflammation Biology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
  • 5. Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, California, USA.
  • 6. Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, California, USA. Electronic address: [email protected].
PMID: 34808237 DOI: 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 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.

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