Signaling via the IL-20 receptor inhibits cutaneous production of IL-1β and IL-17A to promote infection with methicillin-resistant Staphylococcus aureus

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Abstract

Staphylococcus aureus causes most infections of human skin and soft tissue and is a major infectious cause of mortality. Host defense mechanisms against S. aureus are incompletely understood. Interleukin 19 (IL-19), IL-20 and IL-24 signal through type I and type II IL-20 receptors and are associated with inflammatory skin diseases such as psoriasis and atopic dermatitis. We found here that those cytokines promoted cutaneous infection with S. aureus in mice by downregulating IL-1β- and IL-17A-dependent pathways. We noted similar effects of those cytokines in human keratinocytes after exposure to S. aureus, and antibody blockade of the IL-20 receptor improved outcomes in infected mice. Our findings identify an immunosuppressive role for IL-19, IL-20 and IL-24 during infection that could be therapeutically targeted to alter susceptibility to infection.

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Figure 1: IL-20RB deficiency results in diminished cutaneous infection with MRSA.
Figure 2: Recombinant IL-20R cytokines enhance cutaneous infection with MRSA.
Figure 3: IL-20R signaling suppresses the IL-17A response to infection with MRSA.
Figure 4: The IL-20R cytokines suppress transcription of the gene encoding pro-IL-1β.
Figure 5: Signaling via IL-20R sumoylates C/EBP-β.
Figure 6: Recombinant IL-1β reverses IL-20R-induced susceptibility to S. aureus.
Figure 7: The IL-20R cytokines are induced by S. aureus in human keratinocytes and can be therapeutically blocked in the mouse skin-infection model.

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Acknowledgements

We thank Y. Iwakura (University of Tokyo) for Il17a−/− mice; J. O'Shea (National Institute of Arthritis, Musculoskeletal and Skin Diseases) for Stat3WT/ΔV463 mice; F. DeLeo (Rocky Mountain Labs, National Institute of Allergy and Infectious Diseases) for the clinical isolate of MRSA USA300 (LAC strain); A. Costanzo and J. Jameson (The Scripps Research Institute) for PAM 2-12 cells; A. Coxon (National Cancer Institute) for foreskin samples; and F. DeLeo and J. O'Shea for critical reading of the manuscript. Supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (US National Institutes of Health).

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I.A.M. designed, did and analyzed the experiments, and wrote the manuscript; N.M.F., P.A.V. and P.J.V. assisted with experiments; S.N. and Y.B. assisted with acquisition and analysis of skin cell flow cytometry; W.O. provided Il20rb−/− and Il22−/− mice; S.K.D. oversaw design and analysis of the experiments and wrote the manuscript; and all authors critically read the manuscript.

Corresponding author

Correspondence to Sandip K Datta.

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W.O. is an employee of Genentech.

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Myles, I., Fontecilla, N., Valdez, P. et al. Signaling via the IL-20 receptor inhibits cutaneous production of IL-1β and IL-17A to promote infection with methicillin-resistant Staphylococcus aureus. Nat Immunol 14, 804–811 (2013). https://doi.org/10.1038/ni.2637

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