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Author Notes:

For correspondence j.silke@latrobe.edu.au

See publication for full list of author contributions

We thank staff in The Walter and Eliza Hall Institute of Medical Research (WEHI) and UCL Bioservices facilities, the WEHI Histology department and FACS lab, Vishva Dixit for Ripk3−/− mice, Vishva Dixit and Domagoj Vucic for the linear-ubiquitin-specific antibody, Heinrich Korner for Tnf−/−, Tnfr1−/−, and Tnfr2 −/− mice, Stephen Hedrick and Razqallah Hakem for Casp8fl/fl, Philippe Bouillet for Bid−/−, and Dr M Labow for Il1r1−/− mice.

We thank Julia Zinngrebe for technical assistance and George Varigos for discussions and support.

The authors declare that no competing interests exist.

Animal experimentation: Animal experiments were performed in strict accordance with the WEHI Animal Ethics Committee and Institute guidelines.

All procedures were specifically approved under WEHI Ethics Project Number 2011.013.

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Research Funding:

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.

Further individual grant information available in the publication.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biology
  • Life Sciences & Biomedicine - Other Topics
  • CHRONIC PROLIFERATIVE DERMATITIS
  • CHAIN ASSEMBLY COMPLEX
  • MIXED LINEAGE KINASE
  • KAPPA-B ACTIVITY
  • NLRP3 INFLAMMASOME
  • LYMPHOTOXIN-ALPHA
  • CUTTING EDGE
  • RIP3 KINASE
  • DOMAIN-LIKE
  • APOPTOSIS

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

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Journal Title:

eLife

Volume:

Volume 3

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Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2014, Rickard et al

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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