TY - JOUR
T1 - Divergent effects of RIP1 or RIP3 blockade in murine models of acute liver injury
AU - Deutsch, M.
AU - Graffeo, C. S.
AU - Rokosh, R.
AU - Pansari, M.
AU - Ochi, A.
AU - Levie, E. M.
AU - Van Heerden, E.
AU - Tippens, D. M.
AU - Greco, S.
AU - Barilla, R.
AU - Tomkötter, L.
AU - Zambirinis, C. P.
AU - Avanzi, N.
AU - Gulati, R.
AU - Pachter, H. L.
AU - Torres-Hernandez, A.
AU - Eisenthal, A.
AU - Daley, D.
AU - Miller, G.
N1 - Publisher Copyright:
© 2015 Macmillan Publishers Limited All rights reserved.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84970916712&partnerID=8YFLogxK
U2 - 10.1038/cddis.2015.126
DO - 10.1038/cddis.2015.126
M3 - Article
C2 - 25950489
AN - SCOPUS:84970916712
SN - 2041-4889
VL - 6
SP - e1759
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 5
M1 - e1759
ER -
