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Sci Transl Med. 2017 Oct 11;9(411). pii: eaan2514. doi: 10.1126/scitranslmed.aan2514.

An analysis of IL-36 signature genes and individuals with IL1RL2 knockout mutations validates IL-36 as a psoriasis therapeutic target.

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Division of Genetics and Molecular Medicine, King's College London, London SE1 9RT, UK.
Cancer Systems Biology Laboratory, Francis Crick Institute, London NW1 1AT, UK.
AhRimmunity Laboratory, Francis Crick Institute, London NW1 1AT, UK.
UCL Institute of Child Health, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
School of Medicine, University of Leeds, Leeds, LS9 7TF, UK.
Department of Immunobiology, King's College London, London SE1 9RT, UK.
Bradford Royal Infirmary, Bradford Institute for Health Research, Bradford BD9 6RJ, UK.
Division of Cancer Studies, King's College London, London SE1 1UL, UK.
Division of Genetics and Molecular Medicine, King's College London, London SE1 9RT, UK.


Interleukin (IL)-36α, IL-36β, and IL-36γ are innate mediators of acute epithelial inflammation. We sought to demonstrate that these cytokines are also required for the pathogenesis of plaque psoriasis, a common and chronic skin disorder, caused by abnormal T helper 17 (TH17) cell activation. To investigate this possibility, we first defined the genes that are induced by IL-36 cytokines in primary human keratinocytes. This enabled us to demonstrate a significant IL-36 signature among the transcripts that are up-regulated in plaque psoriasis and the susceptibility loci associated with the disease in genome-wide studies. Next, we investigated the impact of in vivo and ex vivo IL-36 receptor blockade using a neutralizing antibody or a recombinant antagonist. Both inhibitors had marked anti-inflammatory effects on psoriatic skin, demonstrated by statistically significant reductions in IL-17 expression, keratinocyte activation, and leukocyte infiltration. Finally, we explored the potential safety profile associated with IL-36 blockade by phenotyping 12 individuals carrying knockout mutations of the IL-36 receptor gene. We found that normal immune function was broadly preserved in these individuals, suggesting that IL-36 signaling inhibition would not substantially compromise host defenses. These observations, which integrate the results of transcriptomics and model system analysis, pave the way for early-stage clinical trials of IL-36 antagonists.

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