Journal article
TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice
- Rickard, James A Department of Medical Biology, University of Melbourne, Parkville, Australia
- Anderton, Holly Department of Medical Biology, University of Melbourne, Parkville, Australia
- Etemadi, Nima Department of Medical Biology, University of Melbourne, Parkville, Australia
- Nachbur, Ueli Department of Medical Biology, University of Melbourne, Parkville, Australia
- Darding, Maurice Centre for Cell Death, Cancer, and Inflammation, University College London, London, United Kingdom
- Peltzer, Nieves Centre for Cell Death, Cancer, and Inflammation, University College London, London, United Kingdom
- Lalaoui, Najoua Department of Medical Biology, University of Melbourne, Parkville, Australia
- Lawlor, Kate E Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
- Vanyai, Hannah Development and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
- Hall, Cathrine Department of Medical Biology, University of Melbourne, Parkville, Australia
- Bankovacki, Aleks Department of Medical Biology, University of Melbourne, Parkville, Australia
- Gangoda, Lahiru Department of Biochemistry, La Trobe University, Bundoora, Australia
- Wong, Wendy Wei-Lynn Department of Immunology, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
- Corbin, Jason Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
- Huang, Chunzi Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, United States
- Mocarski, Edward S Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, United States
- Murphy, James M Department of Medical Biology, University of Melbourne, Parkville, Australia
- Alexander, Warren S Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
- Voss, Anne K Development and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
- Vaux, David L Department of Medical Biology, University of Melbourne, Parkville, Australia
- Kaiser, William J Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, United States
- Walczak, Henning Centre for Cell Death, Cancer, and Inflammation, University College London, London, United Kingdom
- Silke, John Department of Medical Biology, University of Melbourne, Parkville, Australia
- 2014-12-2
Published in:
- eLife. - eLife Sciences Publications, Ltd. - 2014, vol. 3
English
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.
- Language
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- English
- Open access status
- gold
- Identifiers
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- DOI 10.7554/elife.03464
- ISSN 2050-084X
- Persistent URL
- https://sonar.ch/global/documents/103174
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