CARD14E138A signalling in keratinocytes induces TNF-dependent skin and systemic inflammation.
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
To investigate how the CARD14E138A psoriasis-associated mutation induces skin inflammation, a knock-in mouse strain was generated that allows tamoxifen-induced expression of the homologous Card14E138A mutation from the endogenous mouse Card14 locus. Heterozygous expression of CARD14E138A rapidly induced skin acanthosis, immune cell infiltration and expression of psoriasis-associated pro-inflammatory genes. Homozygous expression of CARD14E138A induced more extensive skin inflammation and a severe systemic disease involving infiltration of myeloid cells in multiple organs, temperature reduction, weight loss and organ failure. This severe phenotype resembled acute exacerbations of generalised pustular psoriasis (GPP), a rare form of psoriasis that can be caused by CARD14 mutations in patients. CARD14E138A-induced skin inflammation and systemic disease were independent of adaptive immune cells, ameliorated by blocking TNF and induced by CARD14E138A signalling only in keratinocytes. These results suggest that anti-inflammatory therapies specifically targeting keratinocytes, rather than systemic biologicals, might be effective for GPP treatment early in disease progression.
Date Issued
2020-06-29
Date Acceptance
2020-06-26
Journal / Book Title
Elife
Volume
9
Copyright Statement
Copyright Manils et al. This
article is distributed under the
terms of the Creative Commons
Attribution License, which
permits unrestricted use and
redistribution provided that the
original author and source are
credited.
article is distributed under the
terms of the Creative Commons
Attribution License, which
permits unrestricted use and
redistribution provided that the
original author and source are
credited.
License URL
Sponsor
The Francis Crick Institute Limited
National Psoriasis Foundation
National Psoriasis Foundation
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/32597759
56720
Grant Number
CR2018/002CH; PO60157091
N/A
Subjects
CARD14
TNF
immunology
inflammation
keratinocytes
mouse
nf-kb
psoriasis
0601 Biochemistry and Cell Biology
Publication Status
Published online
Coverage Spatial
England