CARD14E138A signalling in keratinocytes induces TNF-dependent skin and systemic inflammation
- The Francis Crick Institute, United Kingdom
- Imperial College London, United Kingdom
- Icahn School of Medicine at Mount Sinai, United States
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 generalized 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.
Data availability
The RNA-Seq data generated in this article was deposited in the GEO repository (GSE149880).
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Expression analysis of WT or Card14E138A ears 5 days and 1 month after injecton of tamoxifen.NCBI Gene Expression Omnibus, GSE149880.
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A spatio-temporal characterization of the transcriptional landscape of epidermal developmentNCBI Gene Expression Omnibus, GSE75931.
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RNA-sequencing transcriptome profiling of normal human keratinocytes differentiationNCBI Gene Expression Omnibus, GSE73305.
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A LncRNA-MAF/MAFB transcription factor network regulates epidermal differentiationNCBI Gene Expression Omnibus, GSE52954.
Article and author information
Author details
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
© 2020, Manils et al.
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.
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CARD14E138A signalling in keratinocytes induces TNF-dependent skin and systemic inflammation
eLife 9:e56720.
https://doi.org/10.7554/eLife.56720
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