Divergent effects of RIP1 or RIP3 blockade in murine models of acute liver injury

M. Deutsch, C. S. Graffeo, R. Rokosh, M. Pansari, A. Ochi, E. M. Levie, E. Van Heerden, D. M. Tippens, S. Greco, R. Barilla, L. Tomkötter, C. P. Zambirinis, N. Avanzi, R. Gulati, H. L. Pachter, A. Torres-Hernandez, A. Eisenthal, D. Daley, G. Miller

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Abstract

Necroptosis is a recently described Caspase 8-independent method of cell death that denotes organized cellular necrosis. The roles of RIP1 and RIP3 in mediating hepatocyte death from acute liver injury are incompletely defined. Effects of necroptosis blockade were studied by separately targeting RIP1 and RIP3 in diverse murine models of acute liver injury. Blockade of necroptosis had disparate effects on disease outcome depending on the precise etiology of liver injury and component of the necrosome targeted. In ConA-induced autoimmune hepatitis, RIP3 deletion was protective, whereas RIP1 inhibition exacerbated disease, accelerated animal death, and was associated with increased hepatocyte apoptosis. Conversely, in acetaminophenmediated liver injury, blockade of either RIP1 or RIP3 was protective and was associated with lower NLRP3 inflammasome activation. Our work highlights the fact that diverse modes of acute liver injury have differing requirements for RIP1 and RIP3; moreover, within a single injury model, RIP1 and RIP3 blockade can have diametrically opposite effects on tissue damage, suggesting that interference with distinct components of the necrosome must be considered separately.

Original languageEnglish (US)
Article numbere1759
JournalCell Death and Disease
Volume6
Issue number5
DOIs
StatePublished - May 1 2015

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All Science Journal Classification (ASJC) codes

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Deutsch, M., Graffeo, C. S., Rokosh, R., Pansari, M., Ochi, A., Levie, E. M., Van Heerden, E., Tippens, D. M., Greco, S., Barilla, R., Tomkötter, L., Zambirinis, C. P., Avanzi, N., Gulati, R., Pachter, H. L., Torres-Hernandez, A., Eisenthal, A., Daley, D., & Miller, G. (2015). Divergent effects of RIP1 or RIP3 blockade in murine models of acute liver injury. Cell Death and Disease, 6(5), [e1759]. https://doi.org/10.1038/cddis.2015.126