CCR6 is required for IL-23-induced psoriasis-like inflammation in mice

Michael N. Hedrick, Anke S. Lonsdorf, Aiko Konno Shirakawa, Chyi Chia Richard Lee, Fang Liao, Satya P. Singh, Hongwei H. Zhang, Alexander Grinberg, Paul E. Love, Samuel T Hwang, Joshua M. Farber

Research output: Contribution to journalArticle

150 Citations (Scopus)

Abstract

Psoriasis is a common immune-mediated chronic inflammatory skin disorder, but the mechanisms of pathogenesis are still poorly understood. IL-23 is expressed in psoriatic skin, and IL-23 injection produces IL-22-dependent psoriasiform changes in mouse skin. Th17 cells produce IL-22 and display CCR6, the CCL20 receptor; CCR6+ T cells and CCL20 are abundant in psoriatic skin. We investigated a possible role for CCR6 in recruiting Th17 cells and producing psoriasiform pathology by injecting IL-23 into the skin of WT and Ccr6 -/- mice. Unlike for WT mice, IL-23-injected ears of Ccr6 -/- mice showed neither substantial epidermal/dermal changes nor increased Il22 mRNA expression. However, injection of IL-22 yielded equivalent psoriasiform changes in WT and Ccr6-/- mice. Surprisingly, IL-23-injected ears of WT and Ccr6-/- mice contained similar numbers of Th cells able to make IL-17A and/or IL-22. Furthermore, in ears of Rag1 -/- mice, IL-23 initially induced skin changes and levels of Il22 mRNA that were indistinguishable from WT mice, revealing at least one non-T cell source for IL-22. We conclude that CCR6 is essential in a model of IL-23-induced, IL-22-mediated dermatitis, which develops in sequential T cell-independent and T cell-dependent phases. These findings reveal an expanded role for CCR6 in IL-23-related responses and identify CCR6 as a potential therapeutic target in psoriasis.

Original languageEnglish (US)
Pages (from-to)2317-2329
Number of pages13
JournalJournal of Clinical Investigation
Volume119
Issue number8
DOIs
StatePublished - Aug 3 2009
Externally publishedYes

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Interleukin-23
Psoriasis
Inflammation
Skin
Ear
Th17 Cells
T-Lymphocytes
CCR6 Receptors
Messenger RNA
Injections
Interleukin-17
Dermatitis
interleukin-22
Cell Count
Pathology

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Hedrick, M. N., Lonsdorf, A. S., Shirakawa, A. K., Lee, C. C. R., Liao, F., Singh, S. P., ... Farber, J. M. (2009). CCR6 is required for IL-23-induced psoriasis-like inflammation in mice. Journal of Clinical Investigation, 119(8), 2317-2329. https://doi.org/10.1172/JCI37378

CCR6 is required for IL-23-induced psoriasis-like inflammation in mice. / Hedrick, Michael N.; Lonsdorf, Anke S.; Shirakawa, Aiko Konno; Lee, Chyi Chia Richard; Liao, Fang; Singh, Satya P.; Zhang, Hongwei H.; Grinberg, Alexander; Love, Paul E.; Hwang, Samuel T; Farber, Joshua M.

In: Journal of Clinical Investigation, Vol. 119, No. 8, 03.08.2009, p. 2317-2329.

Research output: Contribution to journalArticle

Hedrick, MN, Lonsdorf, AS, Shirakawa, AK, Lee, CCR, Liao, F, Singh, SP, Zhang, HH, Grinberg, A, Love, PE, Hwang, ST & Farber, JM 2009, 'CCR6 is required for IL-23-induced psoriasis-like inflammation in mice', Journal of Clinical Investigation, vol. 119, no. 8, pp. 2317-2329. https://doi.org/10.1172/JCI37378
Hedrick MN, Lonsdorf AS, Shirakawa AK, Lee CCR, Liao F, Singh SP et al. CCR6 is required for IL-23-induced psoriasis-like inflammation in mice. Journal of Clinical Investigation. 2009 Aug 3;119(8):2317-2329. https://doi.org/10.1172/JCI37378
Hedrick, Michael N. ; Lonsdorf, Anke S. ; Shirakawa, Aiko Konno ; Lee, Chyi Chia Richard ; Liao, Fang ; Singh, Satya P. ; Zhang, Hongwei H. ; Grinberg, Alexander ; Love, Paul E. ; Hwang, Samuel T ; Farber, Joshua M. / CCR6 is required for IL-23-induced psoriasis-like inflammation in mice. In: Journal of Clinical Investigation. 2009 ; Vol. 119, No. 8. pp. 2317-2329.
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abstract = "Psoriasis is a common immune-mediated chronic inflammatory skin disorder, but the mechanisms of pathogenesis are still poorly understood. IL-23 is expressed in psoriatic skin, and IL-23 injection produces IL-22-dependent psoriasiform changes in mouse skin. Th17 cells produce IL-22 and display CCR6, the CCL20 receptor; CCR6+ T cells and CCL20 are abundant in psoriatic skin. We investigated a possible role for CCR6 in recruiting Th17 cells and producing psoriasiform pathology by injecting IL-23 into the skin of WT and Ccr6 -/- mice. Unlike for WT mice, IL-23-injected ears of Ccr6 -/- mice showed neither substantial epidermal/dermal changes nor increased Il22 mRNA expression. However, injection of IL-22 yielded equivalent psoriasiform changes in WT and Ccr6-/- mice. Surprisingly, IL-23-injected ears of WT and Ccr6-/- mice contained similar numbers of Th cells able to make IL-17A and/or IL-22. Furthermore, in ears of Rag1 -/- mice, IL-23 initially induced skin changes and levels of Il22 mRNA that were indistinguishable from WT mice, revealing at least one non-T cell source for IL-22. We conclude that CCR6 is essential in a model of IL-23-induced, IL-22-mediated dermatitis, which develops in sequential T cell-independent and T cell-dependent phases. These findings reveal an expanded role for CCR6 in IL-23-related responses and identify CCR6 as a potential therapeutic target in psoriasis.",
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AU - Lonsdorf, Anke S.

AU - Shirakawa, Aiko Konno

AU - Lee, Chyi Chia Richard

AU - Liao, Fang

AU - Singh, Satya P.

AU - Zhang, Hongwei H.

AU - Grinberg, Alexander

AU - Love, Paul E.

AU - Hwang, Samuel T

AU - Farber, Joshua M.

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N2 - Psoriasis is a common immune-mediated chronic inflammatory skin disorder, but the mechanisms of pathogenesis are still poorly understood. IL-23 is expressed in psoriatic skin, and IL-23 injection produces IL-22-dependent psoriasiform changes in mouse skin. Th17 cells produce IL-22 and display CCR6, the CCL20 receptor; CCR6+ T cells and CCL20 are abundant in psoriatic skin. We investigated a possible role for CCR6 in recruiting Th17 cells and producing psoriasiform pathology by injecting IL-23 into the skin of WT and Ccr6 -/- mice. Unlike for WT mice, IL-23-injected ears of Ccr6 -/- mice showed neither substantial epidermal/dermal changes nor increased Il22 mRNA expression. However, injection of IL-22 yielded equivalent psoriasiform changes in WT and Ccr6-/- mice. Surprisingly, IL-23-injected ears of WT and Ccr6-/- mice contained similar numbers of Th cells able to make IL-17A and/or IL-22. Furthermore, in ears of Rag1 -/- mice, IL-23 initially induced skin changes and levels of Il22 mRNA that were indistinguishable from WT mice, revealing at least one non-T cell source for IL-22. We conclude that CCR6 is essential in a model of IL-23-induced, IL-22-mediated dermatitis, which develops in sequential T cell-independent and T cell-dependent phases. These findings reveal an expanded role for CCR6 in IL-23-related responses and identify CCR6 as a potential therapeutic target in psoriasis.

AB - Psoriasis is a common immune-mediated chronic inflammatory skin disorder, but the mechanisms of pathogenesis are still poorly understood. IL-23 is expressed in psoriatic skin, and IL-23 injection produces IL-22-dependent psoriasiform changes in mouse skin. Th17 cells produce IL-22 and display CCR6, the CCL20 receptor; CCR6+ T cells and CCL20 are abundant in psoriatic skin. We investigated a possible role for CCR6 in recruiting Th17 cells and producing psoriasiform pathology by injecting IL-23 into the skin of WT and Ccr6 -/- mice. Unlike for WT mice, IL-23-injected ears of Ccr6 -/- mice showed neither substantial epidermal/dermal changes nor increased Il22 mRNA expression. However, injection of IL-22 yielded equivalent psoriasiform changes in WT and Ccr6-/- mice. Surprisingly, IL-23-injected ears of WT and Ccr6-/- mice contained similar numbers of Th cells able to make IL-17A and/or IL-22. Furthermore, in ears of Rag1 -/- mice, IL-23 initially induced skin changes and levels of Il22 mRNA that were indistinguishable from WT mice, revealing at least one non-T cell source for IL-22. We conclude that CCR6 is essential in a model of IL-23-induced, IL-22-mediated dermatitis, which develops in sequential T cell-independent and T cell-dependent phases. These findings reveal an expanded role for CCR6 in IL-23-related responses and identify CCR6 as a potential therapeutic target in psoriasis.

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