TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice
- Author(s)
- Rickard, James A; Anderton, Holly; Etemadi, Nima; Nachbur, Ueli; Darding, Maurice; Peltzer, Nieves; Lalaoui, Najoua; Lawlor, Kate E; Vanyai, Hannah; Hall, Cathrine; Bankovacki, Aleks; Gangoda, Lahiru; Wong, Wendy Wei-Lynn; Corbin, Jason; Huang, Chunzi; Mocarski, Edward S; Murphy, James M; Alexander, Warren S; Voss, Anne K; Vaux, David L; Kaiser, William J; Walczak, Henning; Silke, John;
- Journal Title
- ELife
- Publication Type
- Journal Article
- Abstract
- SHARPIN regulates immune signaling and contributes to full transcriptional activity and prevention of cell death in response to TNF in vitro. The inactivating mouse Sharpin cpdm mutation causes TNF-dependent multi-organ inflammation, characterized by dermatitis, liver inflammation, splenomegaly, and loss of Peyer's patches. TNF-dependent cell death has been proposed to cause the inflammatory phenotype and consistent with this we show Tnfr1, but not Tnfr2, deficiency suppresses the phenotype (and it does so more efficiently than Il1r1 loss). TNFR1-induced apoptosis can proceed through caspase-8 and BID, but reduction in or loss of these players generally did not suppress inflammation, although Casp8 heterozygosity significantly delayed dermatitis. Ripk3 or Mlkl deficiency partially ameliorated the multi-organ phenotype, and combined Ripk3 deletion and Casp8 heterozygosity almost completely suppressed it, even restoring Peyer's patches. Unexpectedly, Sharpin, Ripk3 and Casp8 triple deficiency caused perinatal lethality. These results provide unexpected insights into the developmental importance of SHARPIN.
- Publisher
- eLife Sciences Publications
- Keywords
- LUBAC; TNF signaling; apoptosis; cell biology; dermatitis; developmental biology; inflammation; mouse; stem cells; ubiquitin
- Research Division(s)
- Cell Signalling And Cell Death; Inflammation; Development And Cancer; Cancer And Haematology
- Publisher's Version
- https://doi.org/10.7554/eLife.03464
- Open Access at Publisher's Site
http://elifesciences.org/content/3/e03464- Terms of Use/Rights Notice
- Copyright © 2014, Rickard et al This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Creation Date: 2014-12-03 09:45:49
Last Modified: 2014-12-04 09:32:21