| First Author | Manils J | Year | 2020 |
| Journal | Elife | Volume | 9 |
| PubMed ID | 32597759 | Mgi Jnum | J:291840 |
| Mgi Id | MGI:6445444 | Doi | 10.7554/eLife.56720 |
| Citation | Manils J, et al. (2020) CARD14(E138A) signalling in keratinocytes induces TNF-dependent skin and systemic inflammation. Elife 9:e56720 |
| abstractText | To investigate how the CARD14(E138A) psoriasis-associated mutation induces skin inflammation, a knock-in mouse strain was generated that allows tamoxifen-induced expression of the homologous Card14(E138A) mutation from the endogenous mouse Card14 locus. Heterozygous expression of CARD14(E138A) rapidly induced skin acanthosis, immune cell infiltration and expression of psoriasis-associated pro-inflammatory genes. Homozygous expression of CARD14(E138A) 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. CARD14(E138A)-induced skin inflammation and systemic disease were independent of adaptive immune cells, ameliorated by blocking TNF and induced by CARD14(E138A) 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. |
