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Proc Natl Acad Sci U S A. 2017 Nov 21;114(47):12460-12465. doi: 10.1073/pnas.1704958114. Epub 2017 Nov 6.

Protein engineering of the chemokine CCL20 prevents psoriasiform dermatitis in an IL-23-dependent murine model.

Author information

1
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226.
2
Department of Dermatology, Medical College of Wisconsin, Milwaukee, WI 53226.
3
Department of Dermatology, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
4
Laboratory for Molecular Pharmacology, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, The Panum Institute, University of Copenhagen, DK-2200 Copenhagen, Denmark.
5
Department of Dermatology, University of California Davis School of Medicine, Sacramento, CA 95816.
6
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226; bvolkman@mcw.edu.

Abstract

Psoriasis is a chronic inflammatory skin disease characterized by the infiltration of T cell and other immune cells to the skin in response to injury or autoantigens. Conventional, as well as unconventional, γδ T cells are recruited to the dermis and epidermis by CCL20 and other chemokines. Together with its receptor CCR6, CCL20 plays a critical role in the development of psoriasiform dermatitis in mouse models. We screened a panel of CCL20 variants designed to form dimers stabilized by intermolecular disulfide bonds. A single-atom substitution yielded a CCL20 variant (CCL20 S64C) that acted as a partial agonist for the chemokine receptor CCR6. CCL20 S64C bound CCR6 and induced intracellular calcium release, consistent with G-protein activation, but exhibited minimal chemotactic activity. Instead, CCL20 S64C inhibited CCR6-mediated T cell migration with nominal impact on other chemokine receptor signaling. When given in an IL-23-dependent mouse model for psoriasis, CCL20 S64C prevented psoriatic inflammation and the up-regulation of IL-17A and IL-22. Our results validate CCR6 as a tractable therapeutic target for psoriasis and demonstrate the value of CCL20 S64C as a lead compound.

KEYWORDS:

CCL20; Th17; X-ray; protein engineering; psoriasis

PMID:
29109267
PMCID:
PMC5703275
DOI:
10.1073/pnas.1704958114
[Indexed for MEDLINE]
Free PMC Article

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