eLife (Dec 2014)
TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice
- James A Rickard,
- Holly Anderton,
- Nima Etemadi,
- Ueli Nachbur,
- Maurice Darding,
- Nieves Peltzer,
- Najoua Lalaoui,
- Kate E Lawlor,
- Hannah Vanyai,
- Cathrine Hall,
- Aleks Bankovacki,
- Lahiru Gangoda,
- Wendy Wei-Lynn Wong,
- Jason Corbin,
- Chunzi Huang,
- Edward S Mocarski,
- James M Murphy,
- Warren S Alexander,
- Anne K Voss,
- David L Vaux,
- William J Kaiser,
- Henning Walczak,
- John Silke
Affiliations
- James A Rickard
- Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
- Holly Anderton
- Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
- Nima Etemadi
- Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
- Ueli Nachbur
- Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
- Maurice Darding
- Centre for Cell Death, Cancer, and Inflammation, University College London, London, United Kingdom
- Nieves Peltzer
- Centre for Cell Death, Cancer, and Inflammation, University College London, London, United Kingdom
- Najoua Lalaoui
- Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
- Kate E Lawlor
- Department of Medical Biology, University of Melbourne, Parkville, Australia; Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
- Hannah Vanyai
- Department of Medical Biology, University of Melbourne, Parkville, Australia; Development and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
- Cathrine Hall
- Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
- Aleks Bankovacki
- Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
- Lahiru Gangoda
- Department of Biochemistry, La Trobe University, Bundoora, Australia
- Wendy Wei-Lynn Wong
- Department of Immunology, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
- Jason Corbin
- Department of Medical Biology, University of Melbourne, Parkville, Australia; Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
- Chunzi Huang
- Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, United States
- Edward S Mocarski
- Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, United States
- James M Murphy
- Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
- Warren S Alexander
- Department of Medical Biology, University of Melbourne, Parkville, Australia; Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
- Anne K Voss
- Department of Medical Biology, University of Melbourne, Parkville, Australia; Development and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
- David L Vaux
- Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
- William J Kaiser
- Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, United States
- Henning Walczak
- Centre for Cell Death, Cancer, and Inflammation, University College London, London, United Kingdom
- John Silke
- Cell Signalling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia
- DOI
- https://doi.org/10.7554/eLife.03464
- Journal volume & issue
-
Vol. 3
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.
Keywords
