Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 9, Issue 411, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aan2514
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Funding
- Department of Health via National Institute for Health Research (NIHR) BioResource Clinical Research Facility and comprehensive Biomedical Research Centre at Guy's and St. Thomas' NHS Foundation Trust
- King's College London
- King's College Hospital NHS Foundation Trust
- Wellcome Trust [WT101597, WT 102627]
- Medical Research Council (MRC) [MR/L011808/1]
- MRC [MR/L001543/1]
- Psoriasis Association
- Cancer Research UK
- MRC
- Wellcome Trust
- NIHR
- Medical Research Council [MR/L001543/1, MR/M009017/1, MR/L011808/1] Funding Source: researchfish
- Psoriasis Association [ST2/15, RG2/10] Funding Source: researchfish
- MRC [MR/L001543/1, MR/M009017/1, MR/L011808/1] Funding Source: UKRI
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Interleukin (IL)-36a, IL-36b, and IL-36g 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 (T(H)17) 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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