TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice

• Type of Material: Article
• Authors: James A Rickard, Walter and Eliza Hall Institute of Medical Research; Holly Anderton, Walter and Eliza Hall Institute of Medical Research; Nima Etemadi, Walter and Eliza Hall Institute of Medical Research; Ueli Nachbur, Walter and Eliza Hall Institute of Medical Research; Maurice Darding, University College London; Nieves Peltzer, University College London; Najoua Lalaoui, Walter and Eliza Hall Institute of Medical Research; Kate E Lawlor, University of Melbourne; Hannah Vanyai, University of Melbourne; Cathrine Hall, Walter and Eliza Hall Institute of Medical Research; Aleks Bankovacki, Walter and Eliza Hall Institute of Medical Research; Lahiru Gangoda, La Trobe University; Wendy Wei-Lynn Wong, University of Zurich; Jaspm Corbin, University of Melbourne; Chunzi Huang, Emory University; Edward S Mocarski, Emory University; James M Murphy, Walter and Eliza Hall Institute of Medical Research; Warren S Alexander, University of Melbourne; Anne K Voss, University of Melbourne; David L Vaux, Walter and Eliza Hall Institute of Medical Research; William Kaiser, Emory University; Henning Walczak, University College London; John Silke, Walter and Eliza Hall Institute of Medical Research
• Language: English
• Date: 2014-12-02
• Publisher: eLife Sciences Publications
• Publication Version: Final Published Version
• Copyright Statement: © 2014, Rickard et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.7554/eLife.03464
• Title of Journal or Parent Work: eLife
• ISSN: 2050-084X
• Volume: 3
• Grant/Funding Information: Further individual grant information available in the publication.; This work was supported by the Thomas William and Violet Coles Trust Fund, NHMRC grants (1016647, 461221, 1025594, 1046984, 1046010, 1051210, 1057905), APA scholarships (JAR, HV), ARC Fellowship (JMM) and NHMRC fellowships to AKV, JS and WSA (575512, 541901, 1058190, 1058344), NIH grant to WJK (DP1 OD012198) and ESM (NIH (US PHS grant R01 GM112547)), a Wellcome Trust Senior Investigator Award (096831/Z/11/Z) and an ERC Advanced Grant (294880) to HW with additional support from the Australian Cancer Research Fund, Victorian State Government Operational Infrastructure Support and NHMRC IRIISS grant (361646).; The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
• Keywords: Life Sciences & Biomedicine - Other Topics; CHRONIC PROLIFERATIVE DERMATITIS; Biology; CHAIN ASSEMBLY COMPLEX; APOPTOSIS; Life Sciences & Biomedicine; RIP3 KINASE; NLRP3 INFLAMMASOME; CUTTING EDGE; KAPPA-B ACTIVITY; LYMPHOTOXIN-ALPHA; Science & Technology; MIXED LINEAGE KINASE; DOMAIN-LIKE
• Research Categories: Biology, Cell; Biology, Microbiology; Health Sciences, Immunology

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.