Abstract
Over the last decade, programmed necrosis (or necroptosis) has been implicated as a significant driver of inflammation and pathology in both animal models1 and human disease,2 and as such, there has been a significant amount of interest in developing therapeutics to target this pathway. Within a couple of years after the characterization of necroptosis, receptor-interacting protein (RIP) 1 and RIP3 were identified as the two critical kinases responsible for mediating this form of cell death3,4 and more recent work has shown that the pseudokinase, mixed lineage kinase domain-like protein (MLKL), to be the direct executioner of programmed necrosis.5 Since these initial discoveries, RIP1, RIP3 and MLKL activation have all been synonymous with the onset of necroptosis. Despite some emerging literature describing additional roles for RIP1 and RIP3 kinase activity beyond triggering MLKL activation and necroptosis,6,7 it has largely been assumed by researchers that interventions targeting RIP1, RIP3 or MLKL were interchangeable. However, to this point, there have been no direct and comprehensive comparisons of these key mediators of necroptosis in vivo.
Highlights
Over the last decade, programmed necrosis has been implicated as a significant driver of inflammation and pathology in both animal models[1] and human disease,[2] and as such, there has been a significant amount of interest in developing therapeutics to target this pathway
mixed lineage kinase domain-like protein (MLKL) deficiency offered little to no protection in these models suggesting that RIP1/RIP3dependent signaling, aside from necroptosis, was the primary driver of pathogenesis in these experimental models
This work highlights that MLKL inhibition or inactivation is currently the only direct way to interrogate in isolation the role of necroptosis in driving inflammation and disease pathogenesis, as RIP1 and RIP3 are likely involved in additional biology beyond driving this form of cell death
Summary
Over the last decade, programmed necrosis (or necroptosis) has been implicated as a significant driver of inflammation and pathology in both animal models[1] and human disease,[2] and as such, there has been a significant amount of interest in developing therapeutics to target this pathway. In a tour de force effort using genetic inactivation of kinase activity or deletion of these proteins, the group compared head-to-head the role of RIP1, RIP3 and MLKL in 10 separate in vivo models.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
