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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

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, S T; Volkman, B F.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 47, 2017, p. 12460-12465.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Getschman, AE, Imai, Y, Larsen, O, Peterson, FC, Wu, X, Rosenkilde, MM, Hwang, ST & Volkman, BF 2017, 'Protein engineering of the chemokine CCL20 prevents psoriasiform dermatitis in an IL-23-dependent murine model', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 47, pp. 12460-12465. https://doi.org/10.1073/pnas.1704958114

APA

Getschman, A. E., Imai, Y., Larsen, O., Peterson, F. C., Wu, X., Rosenkilde, M. M., Hwang, S. T., & Volkman, B. F. (2017). Protein engineering of the chemokine CCL20 prevents psoriasiform dermatitis in an IL-23-dependent murine model. Proceedings of the National Academy of Sciences of the United States of America, 114(47), 12460-12465. https://doi.org/10.1073/pnas.1704958114

Vancouver

Getschman AE, Imai Y, Larsen O, Peterson FC, Wu X, Rosenkilde MM et al. Protein engineering of the chemokine CCL20 prevents psoriasiform dermatitis in an IL-23-dependent murine model. Proceedings of the National Academy of Sciences of the United States of America. 2017;114(47):12460-12465. https://doi.org/10.1073/pnas.1704958114

Author

Getschman, A E ; Imai, Y ; Larsen, O ; Peterson, F C ; Wu, X ; Rosenkilde, M. M. ; Hwang, S 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.

Bibtex

@article{ea5877c9f441498f87f52c1eb97b00c5,
title = "Protein engineering of the chemokine CCL20 prevents psoriasiform dermatitis in an IL-23-dependent murine model",
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 = "Getschman, {A E} and Y Imai and O Larsen and Peterson, {F C} and X Wu and Rosenkilde, {M. M.} and Hwang, {S T} and Volkman, {B F}",
year = "2017",
doi = "10.1073/pnas.1704958114",
language = "English",
volume = "114",
pages = "12460--12465",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "The National Academy of Sciences of the United States of America",
number = "47",

}

RIS

TY - JOUR

T1 - Protein engineering of the chemokine CCL20 prevents psoriasiform dermatitis in an IL-23-dependent murine model

AU - Getschman, A E

AU - Imai, Y

AU - Larsen, O

AU - Peterson, F C

AU - Wu, X

AU - Rosenkilde, M. M.

AU - Hwang, S T

AU - Volkman, B F

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.1704958114

DO - 10.1073/pnas.1704958114

M3 - Journal article

C2 - 29109267

VL - 114

SP - 12460

EP - 12465

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 47

ER -

ID: 189624328