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J Invest Dermatol. 2016 Nov;136(11):2251-2259. doi: 10.1016/j.jid.2016.06.618. Epub 2016 Jul 5.

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

Author information

1
Division of Genetics and Molecular Medicine, King's College London, London, UK.
2
MTA-SZTE Dermatological Research Group, Szeged, Hungary.
3
Department of Dermatology, University of Glasgow, Glasgow, UK.
4
Department of Dermatology, Birmingham Children's Hospital, Birmingham, UK.
5
Paediatric Dermatology, Our Lady's Children's Hospital, Dublin, Ireland.
6
Department of Dermatology and Allergology, University of Szeged, Hungary.
7
Dokumentationszentrum schwerer Hautreaktionen (dZh) and RegiSCAR-study, Department of Dermatology, Medical Center-University of Freiburg, Freiburg, Germany.
8
National Skin Centre, Singapore.
9
Department of Medical Genomics, Royal Prince Alfred Hospital, Camperdown, Australia.
10
Department of Skin and Allergic Diseases, Helsinki University Central Hospital, Helsinki, Finland.
11
Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
12
Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
13
Department of Dermatology, University Hospital, Galway, Ireland.
14
Department of Dermatology, Henri Mondor Hospital, Paris, France.
15
Department of Dermatology, University of Manchester.
16
Department of Dermatology, Hospital Sultanah Aminah, Johor Bahru, Malaysia.
17
MTA-SZTE Dermatological Research Group, Szeged, Hungary; Institute of Medical Genetics, University of Szeged, Hungary.
18
MTA-SZTE Dermatological Research Group, Szeged, Hungary; Department of Dermatology and Allergology, University of Szeged, Hungary.
19
Mill Hill Laboratory, The Francis Crick Institute, London, UK.
20
Division of Genetics and Molecular Medicine, King's College London, London, UK. Electronic address: francesca.capon@kcl.ac.uk.

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.

PMID:
27388993
PMCID:
PMC5070969
DOI:
10.1016/j.jid.2016.06.618
[Indexed for MEDLINE]
Free PMC Article

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