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  • Keratinocytes control skin immune homeostasis through de novo-synthesized glucocorticoids.

Keratinocytes control skin immune homeostasis through de novo-synthesized glucocorticoids.

Science advances (2021-01-31)
Truong San Phan, Leonhard Schink, Jasmin Mann, Verena M Merk, Pascale Zwicky, Sarah Mundt, Dagmar Simon, Dagmar Kulms, Susanne Abraham, Daniel F Legler, Mario Noti, Thomas Brunner
ABSTRACT

Glucocorticoids (GC), synthesized by the 11β-hydroxylase (Cyp11b1), control excessive inflammation through immunosuppressive actions. The skin was proposed to regulate homeostasis by autonomous GC production in keratinocytes. However, their immunosuppressive capacity and clinical relevance remain unexplored. Here, we demonstrate the potential of skin-derived GC and their role in the regulation of physiological and prevalent inflammatory skin conditions. In line with 11β-hydroxylase deficiency in human inflammatory skin disorders, genetic in vivo Cyp11b1 ablation and long-term GC deficiency in keratinocytes primed the murine skin immune system resulting in spontaneous skin inflammation. Deficient skin GC in experimental models for inflammatory skin disorders led to exacerbated contact hypersensitivity and psoriasiform skin inflammation accompanied by decreased regulatory T cells and the involvement of unconventional T cells. Our findings provide insights on how skin homeostasis and pathology are critically regulated by keratinocyte-derived GC, emphasizing the immunoregulatory potential of endogenous GC in the regulation of epithelial immune microenvironment.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Cresyl Violet acetate, certified by the Biological Stain Commission
Sigma-Aldrich
Anti-CYP11B1 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
Sigma-Aldrich
Anti-Keratin 14 antibody produced in rabbit, affinity isolated antibody
Sigma-Aldrich
Fluoroshield with DAPI, histology mounting medium
Sigma-Aldrich
Metyrapone, ≥98% (HPLC), solid
Sigma-Aldrich
Adrenocorticotropic Hormone Fragment 1-24 human, rat, ≥97% (HPLC)
Sigma-Aldrich
Forskolin, For use in molecular biology applications