Abstract
RIP1 kinase-mediated inflammatory and cell death pathways have been implicated in the pathology of acute and chronic disorders of the nervous system. Here, we describe a novel animal model of RIP1 kinase deficiency, generated by knock-in of the kinase-inactivating RIP1(D138N) mutation in rats. Homozygous RIP1 kinase-dead (KD) rats had normal development, reproduction and did not show any gross phenotypes at baseline. However, cells derived from RIP1 KD rats displayed resistance to necroptotic cell death. In addition, RIP1 KD rats were resistant to TNF-induced systemic shock. We studied the utility of RIP1 KD rats for neurological disorders by testing the efficacy of the genetic inactivation in the transient middle cerebral artery occlusion/reperfusion model of brain injury. RIP1 KD rats were protected in this model in a battery of behavioral, imaging, and histopathological endpoints. In addition, RIP1 KD rats had reduced inflammation and accumulation of neuronal injury biomarkers. Unbiased proteomics in the plasma identified additional changes that were ameliorated by RIP1 genetic inactivation. Together these data highlight the utility of the RIP1 KD rats for target validation and biomarker studies for neurological disorders.
Highlights
Proper regulation of cell death is critical for the development and homeostasis in metazoans
Genetic inactivation of RIP1 kinase activity in mice has been instrumental in defining physiological conditions and diseases where RIP1 kinase function plays an important role[17,18,20,22,58]
We have introduced a genetic inactivation of RIP1 kinase function in rats
Summary
Proper regulation of cell death is critical for the development and homeostasis in metazoans. Dysregulation of cell death pathways is associated with a number of human diseases, including cancer, tissue damage/inflammation, and neurodegeneration[1,2]. The best-known form of regulated cell death is apoptosis, which relies on the activation of cysteine proteases called caspases[3]. Necroptosis is activated when caspases are inhibited or insufficiently stimulated[4,5,6]. Necroptosis signaling involves activation of receptor-interacting proteins kinases 1 and 3 (RIP1 and RIP3), and pseudokinase MLKL (mixed lineage kinase-like)[7,8]. In addition to prototypical activation by TNF (tumor necrosis factor), necroptosis can be induced by several members of TNF ligand family, TLR3/4 (toll-like receptors 3/4), viral infection, and tissue damage[9,10]
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