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Protein engineering of the chemokine CCL20 prevents psoriasiform dermatitis in an IL-23-dependent murine model. Proc Natl Acad Sci U S A 2017 11 21;114(47):12460-12465

Date

11/08/2017

Pubmed ID

29109267

Pubmed Central ID

PMC5703275

DOI

10.1073/pnas.1704958114

Scopus ID

2-s2.0-85034572094   11 Citations

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.

Author List

Getschman AE, Imai Y, Larsen O, Peterson FC, Wu X, Rosenkilde MM, Hwang ST, Volkman BF

Authors

Francis C. Peterson PhD Professor in the Biochemistry department at Medical College of Wisconsin
Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Biological Therapy
COS Cells
Chemokine CCL20
Crystallography, X-Ray
Dermatitis
Disease Models, Animal
Epidermis
Humans
Interleukin-23
Mice
Mutagenesis, Site-Directed
Psoriasis
Receptors, CCR6
T-Lymphocytes
jenkins-FCD Prod-444 eb4ebd1a08581aba961d3befd3b851a3c3ec6b46