RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice

• Published in: The Journal of immunology (1950) 2014-05, Vol.192 (12), p.5476-5480
• Main Authors: Berger, Scott B., Kasparcova, Viera, Hoffman, Sandy, Swift, Barb, Dare, Lauren, Schaeffer, Michelle, Capriotti, Carol, Cook, Michael, Finger, Joshua, Hughes-Earle, Angela, Harris, Philip A., Kaiser, William J., Mocarski, Edward S., Bertin, John, Gough, Peter J.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1400499

RIP1 kinase is a key regulator of TNF-induced NFκB activation, apoptosis and necroptosis through its kinase and scaffolding activities. Dissecting the balance of RIP1 kinase activity and scaffolding function in vivo during development and TNF-dependent inflammation has been hampered by the perinatal lethality of RIP1-deficient mice. Here we generated RIP1 kinase-dead ( Ripk1 K45A ) mice and showed they are viable and healthy, indicating that kinase activity of RIP1, but not its scaffolding function, is dispensable for viability and homeostasis. After validating that the Ripk1 K45A mice were specifically protected against necroptotic stimuli in vitro and in vivo , we crossed these mice to SHARPIN-deficient cpdm mice, which develop severe skin and multi-organ inflammation that has been hypothesized to be mediated by TNF-dependent apoptosis and/or necroptosis. Remarkably, crossing Ripk1 K45A mice to the cpdm strain protected against all cpdm -related pathology. Together, these data suggest that RIP1 kinase represents an attractive therapeutic target for TNF-driven inflammatory diseases.