Ectodomain shedding of EGFR ligands and TNFR1 dictates hepatocyte apoptosis during fulminant hepatitis in mice

Aditya Murthy, Virginie Defamie, David S. Smookler, Marco A. Di Grappa, Keisuke Horiuchi, Massimo Federici, Maria Sibilia, Carl P. Blobel, Rama Khokha

Research output: Contribution to journalArticle

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Abstract

The cell death receptor Fas plays a role in the establishment of fulminant hepatitis, a major cause of drug-induced liver failure. Fas activation elicits extrinsic apoptotic and hepatoprotective signals; however, the mechanisms by which these signals are integrated during disease are unknown. Tissue inhibitor of metalloproteinases 3 (TIMP3) controls the critical sheddase a disintegrin and metalloproteinase 17 (ADAM17) and may dictate stress signaling. Using mice and cells lacking TIMP3, ADAM17, and ADAM17-regulated cell surface molecules, we have found that ADAM17-mediated ectodomain shedding of TNF receptors and EGF family ligands controls activation of multiple signaling cascades in Fas-induced hepatitis. We demonstrated that TNF signaling promoted hepatotoxicity, while excessive TNF receptor 1 (TNFR1) shedding in Timp3-/- mice was protective. Compound Timp3-/-Tnf-/- and Timp3 -/-Tnfr1-/- knockout conferred complete resistance to Fas-induced toxicity. Loss of Timp3 enhanced metalloproteinase-dependent EGFR signaling due to increased release of the EGFR ligands TGF-α, amphiregulin, and HB-EGF, while depletion of shed amphiregulin resensitized Timp3-/- hepatocytes to apoptosis. Finally, adenoviral delivery of Adam17 prevented acetaminophen-induced liver failure in a clinically relevant model of Fas-dependent fulminant hepatitis. These findings demonstrate that TIMP3 and ADAM17 cooperatively dictate cytokine signaling during death receptor activation and indicate that regulated metalloproteinase activity integrates survival and death signals during acute hepatotoxic stress.

Original languageEnglish
Pages (from-to)2731-2744
Number of pages14
JournalJournal of Clinical Investigation
Volume120
Issue number8
DOIs
Publication statusPublished - 2010 Aug 2

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Tumor Necrosis Factors
Metalloproteases
Disintegrins
Hepatitis
Hepatocytes
Apoptosis
Tissue Inhibitor of Metalloproteinase-3
Death Domain Receptors
Tumor Necrosis Factor Receptors
Liver Failure
Ligands
Acetaminophen
Epidermal Growth Factor
Cell Death
Cytokines

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Murthy, A., Defamie, V., Smookler, D. S., Di Grappa, M. A., Horiuchi, K., Federici, M., ... Khokha, R. (2010). Ectodomain shedding of EGFR ligands and TNFR1 dictates hepatocyte apoptosis during fulminant hepatitis in mice. Journal of Clinical Investigation, 120(8), 2731-2744. https://doi.org/10.1172/JCI42686

Ectodomain shedding of EGFR ligands and TNFR1 dictates hepatocyte apoptosis during fulminant hepatitis in mice. / Murthy, Aditya; Defamie, Virginie; Smookler, David S.; Di Grappa, Marco A.; Horiuchi, Keisuke; Federici, Massimo; Sibilia, Maria; Blobel, Carl P.; Khokha, Rama.

In: Journal of Clinical Investigation, Vol. 120, No. 8, 02.08.2010, p. 2731-2744.

Research output: Contribution to journalArticle

Murthy, A, Defamie, V, Smookler, DS, Di Grappa, MA, Horiuchi, K, Federici, M, Sibilia, M, Blobel, CP & Khokha, R 2010, 'Ectodomain shedding of EGFR ligands and TNFR1 dictates hepatocyte apoptosis during fulminant hepatitis in mice', Journal of Clinical Investigation, vol. 120, no. 8, pp. 2731-2744. https://doi.org/10.1172/JCI42686
Murthy, Aditya ; Defamie, Virginie ; Smookler, David S. ; Di Grappa, Marco A. ; Horiuchi, Keisuke ; Federici, Massimo ; Sibilia, Maria ; Blobel, Carl P. ; Khokha, Rama. / Ectodomain shedding of EGFR ligands and TNFR1 dictates hepatocyte apoptosis during fulminant hepatitis in mice. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 8. pp. 2731-2744.
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