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.
View: Text | PDF
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

×

Figure 1

Ccr6–/– mice are resistant to IL-23–induced acanthosis and dermal inflammation.

Options: View larger image (or click on image) Download as PowerPoint
Ccr6–/– mice are resistant to IL-23–induced acanthosis and dermal infla...
Ears of WT and Ccr6–/– mice were injected intradermally every other day for 16 days with 20 μl PBS, either alone or containing 500 ng IL-23. (A) Ear thickness was measured on days between injections. Data are from 5 experiments in at least 30 mice/group. **P < 0.01 versus all other groups. (B) H&E-stained sections of PBS- or IL-23–injected ears from WT and Ccr6–/– mice at day 15. k, hyperparakeratosis with intracorneal neutrophilic pustule; a, acanthosis; b, increased proliferative activity of basal layer epidermal keratinocytes; d, dermal mononuclear cell infiltrate; v, telangiectasia of dermal blood vessels. Sections are representative of 2 experiments. (C) Frozen sections of ears from WT PBS-injected or WT and Ccr6–/– IL-23–injected mice on day 15 stained with rat anti-mouse CCL20 or isotype-matched control antibody followed by Alexa Fluor 488–conjugated goat anti-rat IgG (green). Nuclei were counterstained with DAPI. Staining is representative of 2 experiments. (D) mRNA for Ccl20 and Gapdh were measured by real-time RT-PCR at day 15 from ears of WT PBS-injected or WT and Ccr6–/– IL-23–injected mice. Fold changes normalized for Gapdh mRNA are shown versus the PBS-injected ears. Data are from 3 experiments in at least 5 mice/group. *P < 0.05 versus PBS control. Original magnification, ×400.