CARD14E138A signalling in keratinocytes induces TNF-dependent skin and systemic inflammation

Abstract
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Abstract

To investigate how the CARD14^E138A psoriasis-associated mutation induces skin inflammation, a knock-in mouse strain was generated that allows tamoxifen-induced expression of the homologous Card14^E138A mutation from the endogenous mouse Card14 locus. Heterozygous expression of CARD14^E138A rapidly induced skin acanthosis, immune cell infiltration and expression of psoriasis-associated pro-inflammatory genes. Homozygous expression of CARD14^E138A 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 generalized pustular psoriasis (GPP), a rare form of psoriasis that can be caused by CARD14 mutations in patients. CARD14^E138A-induced skin inflammation and systemic disease were independent of adaptive immune cells, ameliorated by blocking TNF and induced by CARD14^E138A 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.

Data availability

The RNA-Seq data generated in this article was deposited in the GEO repository (GSE149880).

The following data sets were generated

1. Manils J
2. Webb L
3. Boeing S
(2020) Expression analysis of WT or Card14E138A ears 5 days and 1 month after injecton of tamoxifen.
NCBI Gene Expression Omnibus, GSE149880.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE149880

The following previously published data sets were used

(2017) A spatio-temporal characterization of the transcriptional landscape of epidermal development
NCBI Gene Expression Omnibus, GSE75931.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE75931
1. Bin L
2. Deng L
3. Yang H
4. Zhu L et al
(2016) RNA-sequencing transcriptome profiling of normal human keratinocytes differentiation
NCBI Gene Expression Omnibus, GSE73305.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE73305
(2014) A LncRNA-MAF/MAFB transcription factor network regulates epidermal differentiation
NCBI Gene Expression Omnibus, GSE52954.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE52954

Article and author information

Author details

Joan Manils

Immune Cell Signaling, The Francis Crick Institute, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-8429-1295
Louise V Webb

Immune Cell Signaling, The Francis Crick Institute, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Ashleigh Howes

National Heart Institute, Imperial College London, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Julia Janzen

Immune Cell Signaling, The Francis Crick Institute, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Stefan Boeing

Bionformatics & Biostatistics Science Technology Platform, The Francis Crick Institute, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Anne M Bowcock

Dermatology, and Genetics & Genome Sciences, Icahn School of Medicine at Mount Sinai, New Yok, United States

For correspondence
anne.bowcock@mssm.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-8691-9090
Steven C Ley

Immunology & Inflammation, Imperial College London, London, United Kingdom

For correspondence
sley@imperial.ac.uk

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-5911-9223

Funding

Francis Crick Institute (FC001103)

Joan Manils
Louise V Webb
Julia Janzen
Stefan Boeing
Steven C Ley

National Psoriasis Foundation (WMIS_P74088)

Joan Manils

British Heart Foundation (PG/15/57/31580)

Louise V Webb

National Institutes of Health (R01AR05026)

Ashleigh Howes
Anne M Bowcock

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Mice were bred and maintained under specific pathogen-free conditions at the Francis Crick 787 Institute. Experiments were performed in accordance with UK Home Office regulations and endorsed by the Francis Crick Institute Animal Welfare and Ethical Review Body under the Procedure Project Licence 70/8819. Rosa26CreERT2 (Seibler et al., 2003), Krt14CreERT2 (Hong et al., 2004), VillinCreERT2 (el Marjou et al., 2004) and Rag1-/- (Spanopoulou et al., 1994) mouse lines have been described previously.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.