The Francis Crick Institute, London, United Kingdom; Department of Immunology & Inflammation, Imperial College London, London, United Kingdom
Louise V Webb
The Francis Crick Institute, London, United Kingdom
Ashleigh Howes
National Heart & Lung Institute, Imperial College London, London, United Kingdom
Julia Janzen
Department of Immunology & Inflammation, Imperial College London, London, United Kingdom
Stefan Boeing
The Francis Crick Institute, London, United Kingdom; Bioinformatics and Biostatistics, The Francis Crick Institute, London, United Kingdom; Crick Scientific Computing - Digital Development Team, The Francis Crick Institute, London, United Kingdom
National Heart & Lung Institute, Imperial College London, London, United Kingdom; Departments of Oncological Science, Dermatology, and Genetics & Genome Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
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.
