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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.

Author information

1
Division of Genetics and Molecular Medicine, King's College London, London SE1 9RT, UK.
2
Cancer Systems Biology Laboratory, Francis Crick Institute, London NW1 1AT, UK.
3
AhRimmunity Laboratory, Francis Crick Institute, London NW1 1AT, UK.
4
UCL Institute of Child Health, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
5
School of Medicine, University of Leeds, Leeds, LS9 7TF, UK.
6
Department of Immunobiology, King's College London, London SE1 9RT, UK.
7
Bradford Royal Infirmary, Bradford Institute for Health Research, Bradford BD9 6RJ, UK.
8
Division of Cancer Studies, King's College London, London SE1 1UL, UK.
9
Division of Genetics and Molecular Medicine, King's College London, London SE1 9RT, UK. francesca.capon@kcl.ac.uk.

Abstract

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.

PMID:
29021166
DOI:
10.1126/scitranslmed.aan2514
[Indexed for MEDLINE]
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