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

  1. Joan Manils
  2. Louise V Webb
  3. Ashleigh Howes
  4. Julia Janzen
  5. Stefan Boeing
  6. Anne M Bowcock  Is a corresponding author
  7. Steven C Ley  Is a corresponding author
  1. The Francis Crick Institute, United Kingdom
  2. Imperial College London, United Kingdom
  3. 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).

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Joan Manils

    Immune Cell Signaling, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8429-1295
  2. Louise V Webb

    Immune Cell Signaling, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Ashleigh Howes

    National Heart Institute, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Julia Janzen

    Immune Cell Signaling, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Stefan Boeing

    Bionformatics & Biostatistics Science Technology Platform, The Francis Crick Institute, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. 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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8691-9090
  7. 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.
    ORCID icon "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.

Reviewing Editor

  1. Carla V Rothlin, Yale School of Medicine, United States

Publication history

  1. Received: March 7, 2020
  2. Accepted: June 26, 2020
  3. Accepted Manuscript published: June 29, 2020 (version 1)
  4. Version of Record published: July 10, 2020 (version 2)

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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  1. Joan Manils
  2. Louise V Webb
  3. Ashleigh Howes
  4. Julia Janzen
  5. Stefan Boeing
  6. Anne M Bowcock
  7. Steven C Ley
(2020)
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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