AP1S3 mutations cause skin autoinflammation by disrupting keratinocyte autophagy and up-regulating IL-36 production

Mahil, S. K. et al. (2016) AP1S3 mutations cause skin autoinflammation by disrupting keratinocyte autophagy and up-regulating IL-36 production. Journal of Investigative Dermatology, 136(11), pp. 2251-2259. (doi: 10.1016/j.jid.2016.06.618)

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-κB activation. We showed that as a consequence, AP1S3-deficient cells up-regulate IL-1 signaling and overexpress IL-36α, 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Burden, Professor David
• Authors: Mahil, S. K., Twelves, S., Farkas, K., Setta-Kaffetzi, N., Burden, A. D., Gach, J. E., Irvine, A. D., Képíró, 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., and Capon, F.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Journal of Investigative Dermatology
• Publisher: Elsevier
• ISSN: 0022-202X
• ISSN (Online): 1523-1747
• Published Online: 12 August 2016
• Copyright Holders: Copyright © 2016 The Authors
• First Published: First published in Journal of Investigative Dermatology 136(11):2251-2259
• Publisher Policy: Reproduced under a Creative Commons License