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

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.

• Authors: 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
• Journal: eLife (Elife) Vol. 3 (Dec 02 2014) ISSN: 2050-084X [Electronic] England
• PMID: 25443632 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Nerve Tissue Proteins
• Receptors, Interleukin-1
• Receptors, Tumor Necrosis Factor, Type I
• Receptors, Tumor Necrosis Factor, Type II
• Tumor Necrosis Factor-alpha
• sharpin
• Rnf31 protein, mouse
• Ubiquitin-Protein Ligases
• Receptor-Interacting Protein Serine-Threonine Kinases
• Ripk3 protein, mouse
• Caspase 3
• Caspase 8

Topics

• Animals
• Caspase 3 (metabolism)
• Caspase 8 (metabolism)
• Cell Death (drug effects)
• Cells, Cultured
• Chronic Disease
• Cytoprotection (drug effects)
• Dermatitis (metabolism, pathology)
• Fibroblasts (drug effects, metabolism, pathology)
• Heterozygote
• Inflammation (metabolism, pathology)
• Keratinocytes (drug effects, metabolism, pathology)
• Liver (drug effects, pathology)
• Macrophages (drug effects, metabolism)
• Mice, Inbred C57BL
• Myeloid Cells (metabolism, pathology)
• Nerve Tissue Proteins (deficiency, metabolism)
• Receptor-Interacting Protein Serine-Threonine Kinases (deficiency, metabolism)
• Receptors, Interleukin-1 (metabolism)
• Receptors, Tumor Necrosis Factor, Type I (metabolism)
• Receptors, Tumor Necrosis Factor, Type II (metabolism)
• Spleen (drug effects, pathology)
• Tumor Necrosis Factor-alpha (pharmacology)
• Ubiquitin-Protein Ligases (metabolism)
• Ubiquitination (drug effects)