Research ArticlePsoriasis

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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Science Translational Medicine  11 Oct 2017:
Vol. 9, Issue 411, eaan2514
DOI: 10.1126/scitranslmed.aan2514

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Nixing IL-36 in psoriasis

Plaque psoriasis is a common T cell–driven autoimmune disease affecting the skin. Targeted biologics impeding the IL-17 inflammatory cytokine family exist but do not provide universal clinical benefit. Mahil et al. convincingly identify IL-36 as an important driver of psoriasis and suggest that blocking IL-36 signaling could bring relief to psoriasis patients. Their results stem from genetic analyses, as well as ex vivo experimentation with patient samples and in vivo treatment of a mouse model. Individuals naturally deficient in IL-36 signaling did not have any overt immunodeficiency, suggesting that interrupting IL-36 would be a safe approach for treating disease.


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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