AP1S3 Mutations Cause Skin Autoinflammation by Disrupting Keratinocyte Autophagy and Up-Regulating IL-36 Production

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Mahil , S K , Twelves , S , Farkas , K , Setta-Kaffetzi , N , Burden , A D , Gach , J E , Irvine , A D , Kepiro , L , Mockenhaupt , M , Oon , H H , Pinner , J , Ranki , A , Seyger , M M B , Soler-Palacin , P , Storan , E R , Tan , E S , Valeyrie-Allanore , L , Young , H S , Trembath , R C , Choon , S-E , Szell , M , Bata-Csorgo , Z , Smith , C H , Di Meglio , P , Barker , J N & Capon , F 2016 , ' AP1S3 Mutations Cause Skin Autoinflammation by Disrupting Keratinocyte Autophagy and Up-Regulating IL-36 Production ' , Journal of Investigative Dermatology , vol. 136 , no. 11 , pp. 2251-2259 . https://doi.org/10.1016/j.jid.2016.06.618

Title: AP1S3 Mutations Cause Skin Autoinflammation by Disrupting Keratinocyte Autophagy and Up-Regulating IL-36 Production
Author: Mahil, Satveer K.; Twelves, Sophie; Farkas, Katalin; Setta-Kaffetzi, Niovi; Burden, A. David; Gach, Joanna E.; Irvine, Alan D.; Kepiro, Laszlo; Mockenhaupt, Maja; Oon, Hazel H.; Pinner, Jason; Ranki, Annamari; Seyger, Marieke M. B.; Soler-Palacin, Pere; Storan, Eoin R.; Tan, Eugene S.; Valeyrie-Allanore, Laurence; Young, Helen S.; Trembath, Richard C.; Choon, Siew-Eng; Szell, Marta; Bata-Csorgo, Zsuzsanna; Smith, Catherine H.; Di Meglio, Paola; Barker, Jonathan N.; Capon, Francesca
Contributor: University of Helsinki, Clinicum
Date: 2016-11
Language: eng
Number of pages: 9
Belongs to series: Journal of Investigative Dermatology
ISSN: 0022-202X
URI: http://hdl.handle.net/10138/169405
Abstract: Prominent skin involvement is a defining characteristic of autoinflammatory disorders caused by abnormal IL-1 signaling. However, the pathways and cell types that drive cutaneous autoinflammatory features remain poorly understood. We sought to address this issue by investigating the pathogenesis of pustular psoriasis, a model of autoinflammatory disorders with predominant cutaneous manifestations. We specifically characterized the impact of mutations affecting AP1S3, a disease gene previously identified by our group and validated here in a newly ascertained patient resource. We first showed that AP1S3 expression is distinctively elevated in keratinocytes. Because AP1S3 encodes a protein implicated in autophagosome formation, we next investigated the effects of gene silencing on this pathway. We found that AP1S3 knockout disrupts keratinocyte autophagy, causing abnormal accumulation of p62, an adaptor protein mediating NF-kappa B activation. We showed that as a consequence, AP1S3-deficient cells up-regulate IL-1 signaling and overexpress IL-36 alpha, a cytokine that is emerging as an important mediator of skin inflammation. These abnormal immune profiles were recapitulated by pharmacological inhibition of autophagy and verified in patient keratinocytes, where they were reversed by IL-36 blockade. These findings show that keratinocytes play a key role in skin autoinflammation and identify autophagy modulation of IL-36 signaling as a therapeutic target.
Subject: GENERALIZED PUSTULAR PSORIASIS
DISEASES
INFLAMMASOMES
INFLAMMATION
ACTIVATION
GENERATION
RESPONSES
3121 General medicine, internal medicine and other clinical medicine
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