CARD14E138A signalling in keratinocytes induces TNF-dependent skin and systemic inflammation. Joan Manils Louise V Webb Ashleigh Howes Julia Janzen Stefan Boeing Anne M Bowcock Steven C Ley 10779/crick.12662084.v1 https://crick.figshare.com/articles/journal_contribution/CARD14E138A_signalling_in_keratinocytes_induces_TNF-dependent_skin_and_systemic_inflammation_/12662084 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. 2020-07-16 12:47:44 immunology inflammation mouse CARD14 TNF keratinocytes nf-kb psoriasis Ley FC001103 CB FC-ack AS-ack BRF-ack HP-ack 0601 Biochemistry and Cell Biology