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

A. E. Getschman, Y. Imai, O. Larsen, F. C. Peterson, X. Wu, M. M. Rosenkilde, Samuel T Hwang, B. F. Volkman

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)12460-12465
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number47
DOIs
StatePublished - Nov 21 2017

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Chemokine CCL20
Protein Engineering
Dermatitis
Psoriasis
Chemokine Receptors
T-Lymphocytes
CCR6 Receptors
Interleukin-17
Autoantigens
Dermis
GTP-Binding Proteins
Skin Diseases
Epidermis
Disulfides
Cell Movement
Up-Regulation
Inflammation
Calcium
Skin
Wounds and Injuries

Keywords

  • CCL20
  • Protein engineering
  • Psoriasis
  • Th17
  • X-ray

ASJC Scopus subject areas

  • General

Cite this

Protein engineering of the chemokine CCL20 prevents psoriasiform dermatitis in an IL-23–dependent murine model. / Getschman, A. E.; Imai, Y.; Larsen, O.; Peterson, F. C.; Wu, X.; Rosenkilde, M. M.; Hwang, Samuel T; Volkman, B. F.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 47, 21.11.2017, p. 12460-12465.

Research output: Contribution to journalArticle

Getschman, A. E. ; Imai, Y. ; Larsen, O. ; Peterson, F. C. ; Wu, X. ; Rosenkilde, M. M. ; Hwang, Samuel T ; Volkman, B. F. / Protein engineering of the chemokine CCL20 prevents psoriasiform dermatitis in an IL-23–dependent murine model. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 47. pp. 12460-12465.
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