CCR6 is required for IL-23–induced psoriasis-like inflammation in mice
Michael N. Hedrick, … , Sam T. Hwang, Joshua M. Farber
Michael N. Hedrick, … , Sam T. Hwang, Joshua M. Farber
Published July 6, 2009
Citation Information: J Clin Invest. 2009;119(8):2317-2329. https://doi.org/10.1172/JCI37378.
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Research Article Dermatology

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

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.

Authors

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, Sam T. Hwang, Joshua M. Farber

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Figure 4

CD4+ T cells from Ccr6–/– mice are able to differentiate into Th17/IL-22–producing cells.

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CD4+ T cells from Ccr6–/– mice are able to differentiate into Th17/IL-22...
(A) Naive CD4+ T cells (CD62L+CD44loCD25–) were purified from WT or Ccr6–/– mice and activated and cultured under nonpolarizing (NP) or Th17-polarizing conditions. After 7 days, cells were treated with PMA and ionomycin, and mRNAs for Il17a, Il22, and Gapdh were measured by real-time RT-PCR. Fold changes were calculated for Il17a and Il22 mRNAs normalized for Gapdh mRNA versus the nonpolarized sample with the greatest ΔCt within each plot. Values denote cells from WT or Ccr6–/– mice from a single representative experiment of 4. (B) Splenocytes were cultured in medium alone or with 100 ng/ml IL-23 for 12 hours, and mRNAs for Il22 and Gapdh were measured by real-time RT-PCR. Fold changes were calculated for values of Il22 mRNA normalized for Gapdh mRNA versus WT cells in medium alone. Data are from 3 samples from WT or Ccr6–/– mice in 1 representative experiment of 2. *P < 0.05 versus medium. Values for IL-23–treated splenocytes from WT and Ccr6–/– mice were not significantly different.