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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/221115
CARD14E138A signalling in keratinocytes induces TNF-dependent skin and systemic inflammation
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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.
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MANILS PACHECO, Joan, WEBB, Louise v., HOWES, Ashleigh, JANZEN, Julia, BOEING, Stefan, BOWCOCK, Anne m., LEY, Steven c.. CARD14E138A signalling in keratinocytes induces TNF-dependent skin and systemic inflammation. _eLife_. 2020. Vol. 9. [consulta: 11 de desembre de 2025]. ISSN: 2050-084X. [Disponible a: https://hdl.handle.net/2445/221115]