Genetic inactivation of RIP1 kinase activity in rats protects against ischemic brain injury.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
07 04 2021
07 04 2021
Historique:
received:
11
01
2021
accepted:
16
03
2021
revised:
11
03
2021
entrez:
8
4
2021
pubmed:
9
4
2021
medline:
13
10
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33828080
doi: 10.1038/s41419-021-03651-6
pii: 10.1038/s41419-021-03651-6
pmc: PMC8026634
doi:
Substances chimiques
Protein Serine-Threonine Kinases
EC 2.7.11.1
RIPK1 protein, rat
EC 2.7.11.1
Receptor-Interacting Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
379Références
Webster, J. D. & Vucic, D. The balance of TNF mediated pathways regulates inflammatory cell death signaling in healthy and diseased tissues. Front. Cell Dev. Biol. 8, 365 (2020).
pubmed: 32671059
pmcid: 7326080
doi: 10.3389/fcell.2020.00365
Heckmann, B. L., Tummers, B. & Green, D. R. Crashing the computer: apoptosis vs. necroptosis in neuroinflammation. Cell Death Differ. 26, 41–52 (2019).
pubmed: 30341422
doi: 10.1038/s41418-018-0195-3
Salvesen, G. S. & Abrams, J. M. Caspase activation - stepping on the gas or releasing the brakes? Lessons from humans and flies. Oncogene 23, 2774–2784 (2004).
pubmed: 15077141
doi: 10.1038/sj.onc.1207522
Li, J. et al. The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell 150, 339–350 (2012).
pubmed: 22817896
pmcid: 3664196
doi: 10.1016/j.cell.2012.06.019
He, S. et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 137, 1100–1111 (2009).
pubmed: 19524512
doi: 10.1016/j.cell.2009.05.021
Cho, Y. S. et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137, 1112–1123 (2009).
pubmed: 19524513
pmcid: 2727676
doi: 10.1016/j.cell.2009.05.037
Newton, K. et al. RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury. Cell Death Differ. 23, 1565–1576 (2016).
pubmed: 27177019
pmcid: 5072432
doi: 10.1038/cdd.2016.46
Degterev, A., Ofengeim, D. & Yuan, J. Targeting RIPK1 for the treatment of human diseases. Proc. Natl Acad. Sci. USA 116, 9714–9722 (2019).
pubmed: 31048504
doi: 10.1073/pnas.1901179116
pmcid: 6525537
Weinlich, R., Oberst, A., Beere, H. M. & Green, D. R. Necroptosis in development, inflammation and disease. Nat. Rev. Mol. Cell Biol. 18, 127–136 (2017).
pubmed: 27999438
doi: 10.1038/nrm.2016.149
Grootjans, S., Vanden Berghe, T. & Vandenabeele, P. Initiation and execution mechanisms of necroptosis: an overview. Cell Death Differ. 24, 1184–1195 (2017).
pubmed: 28498367
pmcid: 5520172
doi: 10.1038/cdd.2017.65
Varfolomeev E. & Vucic D. Intracellular regulation of TNF activity in health and disease. Cytokine 101, 26–32 (2016).
Newton K. & Manning G. Necroptosis and Inflammation. Annu. Rev. Biochem. 85, 743-763 (2016).
Murphy, J. M. et al. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity 39, 443–453 (2013).
pubmed: 24012422
doi: 10.1016/j.immuni.2013.06.018
Sun, L. et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 Kinase. Cell 148, 213–227 (2012).
doi: 10.1016/j.cell.2011.11.031
pubmed: 22265413
Silke, J., Rickard, J. A. & Gerlic, M. The diverse role of RIP kinases in necroptosis and inflammation. Nat. Immunol. 16, 689–697 (2015).
pubmed: 26086143
doi: 10.1038/ni.3206
Vlantis, K. et al. NEMO prevents RIP kinase 1-mediated epithelial cell death and chronic intestinal inflammation by NF-kappaB-dependent and -independent functions. Immunity 44, 553–567 (2016).
pubmed: 26982364
pmcid: 4803910
doi: 10.1016/j.immuni.2016.02.020
Patel, S. et al. RIP1 inhibition blocks inflammatory diseases but not tumor growth or metastases. Cell Death Differ. 27, 161–175 (2020).
pubmed: 31101885
doi: 10.1038/s41418-019-0347-0
Webster, J. D. et al. RIP1 kinase activity is critical for skin inflammation but not for viral propagation. J. Leukoc. Biol. 107, 941–952 (2020).
pubmed: 31985117
doi: 10.1002/JLB.3MA1219-398R
Webster J. D. & Vucic D. The balance of TNF Mediated pathways regulates inflammatory cell death signaling in healthy and diseased tissues. Front. Cell Dev. Biol. 8, 365 (2020).
Berger, S. B. et al. Cutting edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice. J. Immunol. 192, 5476–5480 (2014).
pubmed: 24821972
doi: 10.4049/jimmunol.1400499
Wong, J. et al. RIPK1 mediates TNF-induced intestinal crypt apoptosis during chronic NF-kappaB activation. Cell Mol. Gastroenterol. Hepatol. 9, 295–312 (2020).
pubmed: 31606566
doi: 10.1016/j.jcmgh.2019.10.002
Newton, K. et al. RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury. Cell Death Differ. 23, 1565–1576 (2016).
pubmed: 27177019
pmcid: 5072432
doi: 10.1038/cdd.2016.46
Linkermann, A. et al. Rip1 (receptor-interacting protein kinase 1) mediates necroptosis and contributes to renal ischemia/reperfusion injury. Kidney Int. 81, 751–761 (2012).
pubmed: 22237751
doi: 10.1038/ki.2011.450
Martin-Sanchez, D. et al. TWEAK and RIPK1 mediate a second wave of cell death during AKI. Proc. Natl Acad. Sci. USA 115, 4182–4187 (2018).
pubmed: 29588419
doi: 10.1073/pnas.1716578115
pmcid: 5910825
Anderson, K. R. et al. CRISPR off-target analysis in genetically engineered rats and mice. Nat. methods 15, 512–514 (2018).
pubmed: 29786090
pmcid: 6558654
doi: 10.1038/s41592-018-0011-5
Varfolomeev E., Goncharov T. & Vucic D. Roles of c-IAP proteins in TNF receptor family activation of NF-κB signaling. Methods Mol. Biol. 1280, 269–282 (2015).
Reed, L. W. Modification of the Weil method for myelin using fresh hematoxylin. J. Histotechnol. 8, 205–206 (1985).
doi: 10.1179/his.1985.8.4.205
Callister, S. J. et al. Normalization approaches for removing systematic biases associated with mass spectrometry and label-free proteomics. J. proteome Res. 5, 277–286 (2006).
pubmed: 16457593
pmcid: 1992440
doi: 10.1021/pr050300l
Zhang, Y. et al. Catalytically inactive RIP1 and RIP3 deficiency protect against acute ischemic stroke by inhibiting necroptosis and neuroinflammation. Cell Death Dis. 11, 565 (2020).
pubmed: 32703968
pmcid: 7378260
doi: 10.1038/s41419-020-02770-w
Naito, M. G. et al. Sequential activation of necroptosis and apoptosis cooperates to mediate vascular and neural pathology in stroke. Proc. Natl Acad. Sci. USA 117, 4959–4970 (2020).
pubmed: 32071228
doi: 10.1073/pnas.1916427117
pmcid: 7060720
Bruderer, R. et al. Extending the limits of quantitative proteome profiling with data-independent acquisition and application to acetaminophen-treated three-dimensional liver microtissues. Mol. Cell. Proteom. 14, 1400–1410 (2015).
doi: 10.1074/mcp.M114.044305
Zhang, S. et al. Necrostatin-1 attenuates inflammatory response and improves cognitive function in chronic ischemic stroke mice. Medicines 3, 16 (2016).
pmcid: 5456247
doi: 10.3390/medicines3030016
Ni, Y. et al. RIP1K contributes to neuronal and astrocytic cell death in ischemic stroke via activating autophagic-lysosomal pathway. Neuroscience 371, 60–74 (2018).
pubmed: 29102662
doi: 10.1016/j.neuroscience.2017.10.038
Degterev, A. et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem. Biol. 1, 112–119 (2005).
pubmed: 16408008
doi: 10.1038/nchembio711
Xu, X. et al. Synergistic protective effects of humanin and necrostatin-1 on hypoxia and ischemia/reperfusion injury. Brain Res. 1355, 189–194 (2010).
pubmed: 20682300
pmcid: 3412340
doi: 10.1016/j.brainres.2010.07.080
Li, J. et al. TRAF2 protects against cerebral ischemia-induced brain injury by suppressing necroptosis. Cell death Dis. 10, 1–14 (2019).
Chen, Y. et al. Necrostatin-1 improves long-term functional recovery through protecting oligodendrocyte precursor cells after transient focal cerebral ischemia in mice. Neuroscience 371, 229–241 (2018).
pubmed: 29247776
doi: 10.1016/j.neuroscience.2017.12.007
Li, W. et al. Neuroprotective effects of DTIO, a novel analog of Nec-1, in acute and chronic stages after ischemic stroke. Neuroscience 390, 12–29 (2018).
pubmed: 30076999
doi: 10.1016/j.neuroscience.2018.07.044
Xu, Y. et al. RIP3 induces ischemic neuronal DNA degradation and programmed necrosis in rat via AIF. Sci. Rep. 6, 29362 (2016).
pubmed: 27377128
pmcid: 4932529
doi: 10.1038/srep29362
Yin, B. et al. Inhibition of receptor-interacting protein 3 upregulation and nuclear translocation involved in Necrostatin-1 protection against hippocampal neuronal programmed necrosis induced by ischemia/reperfusion injury. Brain Res. 1609, 63–71 (2015).
pubmed: 25801119
doi: 10.1016/j.brainres.2015.03.024
Yang, R. et al. Necrostatin-1 protects hippocampal neurons against ischemia/reperfusion injury via the RIP3/DAXX signaling pathway in rats. Neurosci. Lett. 651, 207–215 (2017).
pubmed: 28501693
doi: 10.1016/j.neulet.2017.05.016
Tian, J. et al. Combination of emricasan with ponatinib synergistically reduces ischemia/reperfusion injury in rat brain through simultaneous prevention of apoptosis and necroptosis. Transl. Stroke Res. 9, 382–392 (2018).
pubmed: 29103102
doi: 10.1007/s12975-017-0581-z
Deng, X.-X., Li, S.-S. & Sun, F.-Y. Necrostatin-1 prevents necroptosis in brains after ischemic stroke via inhibition of RIPK1-mediated RIPK3/MLKL signaling. Aging Dis. 10, 807 (2019).
pubmed: 31440386
pmcid: 6675533
doi: 10.14336/AD.2018.0728
Shahjouei, S. et al. Middle cerebral artery occlusion model of stroke in rodents: a step-by-step approach. J. Vasc. interv. Neurol. 8, 1 (2016).
pubmed: 26958146
pmcid: 4762402
Barone, F. C., Knudsen, D. J., Nelson, A. H., Feuerstein, G. Z. & Willette, R. N. Mouse strain differences in susceptibility to cerebral ischemia are related to cerebral vascular anatomy. J. Cereb. Blood Flow. Metab. 13, 683–692 (1993).
pubmed: 8314921
doi: 10.1038/jcbfm.1993.87
Riva, M. et al. Hemodynamic monitoring of intracranial collateral flow predicts tissue and functional outcome in experimental ischemic stroke. Exp. Neurol. 233, 815–820 (2012).
pubmed: 22193110
doi: 10.1016/j.expneurol.2011.12.006
Switzer, R. III & Koenig, H. Ischemia contrast stain: a clear way to delineate penumbra following transient focal cerebral ischemia306. J. Neurosurgical Anesthesiol. 7, 310 (1995).
doi: 10.1097/00008506-199510000-00057
Khalil, M. et al. Neurofilaments as biomarkers in neurological disorders. Nat. Rev. Neurol. 14, 577–589 (2018).
pubmed: 30171200
doi: 10.1038/s41582-018-0058-z
De Marchis, G. M. et al. Serum neurofilament light chain in patients with acute cerebrovascular events. Eur. J. Neurol. 25, 562–568 (2018).
pubmed: 29281157
doi: 10.1111/ene.13554
Tiedt, S. et al. Serum neurofilament light: a biomarker of neuroaxonal injury after ischemic stroke. Neurology 91, e1338–e1347 (2018).
pubmed: 30217937
doi: 10.1212/WNL.0000000000006282
Onatsu, J. et al. Serum neurofilament light chain concentration correlates with infarct volume but not prognosis in acute ischemic stroke. J. Stroke Cerebrovasc. Dis. 28, 2242–2249 (2019).
pubmed: 31151840
doi: 10.1016/j.jstrokecerebrovasdis.2019.05.008
Pedersen, A. et al. Circulating neurofilament light in ischemic stroke: temporal profile and outcome prediction. J. Neurol. 266, 2796–2806 (2019).
pubmed: 31375988
pmcid: 6803587
doi: 10.1007/s00415-019-09477-9
Uphaus, T. et al. NfL (neurofilament light chain) levels as a predictive marker for long-term outcome after ischemic. Stroke Stroke 50, 3077–3084 (2019).
pubmed: 31537188
doi: 10.1161/STROKEAHA.119.026410
Wang, P., Fan, J., Yuan, L., Nan, Y. & Nan, S. Serum Neurofilament Light Predicts Severity and Prognosis in Patients with Ischemic Stroke. Neurotox. Res 37, 987–995 (2020).
pubmed: 31898161
doi: 10.1007/s12640-019-00159-y
Liu, D. et al. Serum neurofilament light chain as a predictive biomarker for ischemic stroke outcome: a systematic review and meta-analysis. J. Stroke Cerebrovasc. Dis. 29, 104813 (2020).
pubmed: 32305278
doi: 10.1016/j.jstrokecerebrovasdis.2020.104813
Nielsen, H. H. et al. Acute neurofilament light chain plasma levels correlate with stroke severity and clinical outcome in ischemic stroke patients. Front. Neurol. 11, 448 (2020).
pubmed: 32595585
pmcid: 7300211
doi: 10.3389/fneur.2020.00448
Gendron T. F. et al. Plasma neurofilament light predicts mortality in patients with stroke. Sci. Transl.Med. 12, eaay1913 (2020).
Newton, K. et al. Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science 343, 1357–1360 (2014).
doi: 10.1126/science.1249361
pubmed: 24557836
Harris, P. A. et al. Discovery of a first-in-class receptor interacting protein 1 (RIP1) kinase specific clinical candidate (GSK2982772) for the treatment of inflammatory diseases. J. Med. Chem. 60, 1247–1261 (2017).
pubmed: 28151659
doi: 10.1021/acs.jmedchem.6b01751
Grievink, H. W. et al. DNL104, a centrally penetrant RIPK1 inhibitor, inhibits RIP1 kinase phosphorylation in a randomized phase I ascending dose study in healthy volunteers. Clin. Pharm. Ther. 107, 406–414 (2020).
doi: 10.1002/cpt.1615
Burkhardt, J. E., Ryan, A. M. & Germann, P. G. Practical aspects of discovery pathology. Toxicol. Pathol. 30, 8–10 (2002).
pubmed: 11890479
doi: 10.1080/01926230252824653
Morgan, S. J. et al. Use of animal models of human disease for nonclinical safety assessment of novel pharmaceuticals. Toxicol. Pathol. 41, 508–518 (2013).
pubmed: 22968286
doi: 10.1177/0192623312457273
Chen, A.-Q. et al. Microglia-derived TNF-α mediates endothelial necroptosis aggravating blood brain–barrier disruption after ischemic stroke. Cell Death Dis. 10, 1–18 (2019).
doi: 10.1038/s41419-019-1716-9
Lule S., et al. Cell-specific activation of RIPK1 and MLKL after intracerebral hemorrhage in mice. J. Cereb. Blood Flow. Metab. https://doi.org/10.1177/0271678X20973609 (2020).
Gattringer, T. et al. Serum neurofilament light is sensitive to active cerebral small vessel disease. Neurology 89, 2108–2114 (2017).
pubmed: 29046363
pmcid: 5711505
doi: 10.1212/WNL.0000000000004645
Pujol-Calderón, F. et al. Neurofilament changes in serum and cerebrospinal fluid after acute ischemic stroke. Neurosci. Lett. 698, 58–63 (2019).
pubmed: 30599262
doi: 10.1016/j.neulet.2018.12.042
Carmichael, S. T. Rodent models of focal stroke: size, mechanism, and purpose. NeuroRx 2, 396–409 (2005).
pubmed: 16389304
pmcid: 1144484
doi: 10.1602/neurorx.2.3.396
Sommer, C. J. Ischemic stroke: experimental models and reality. Acta Neuropathol. 133, 245–261 (2017).
pubmed: 28064357
pmcid: 5250659
doi: 10.1007/s00401-017-1667-0
Barry, D. M., Millecamps, S., Julien, J.-P. & Garcia, M. L. New movements in neurofilament transport, turnover and disease. Exp. Cell Res. 313, 2110–2120 (2007).
pubmed: 17451679
doi: 10.1016/j.yexcr.2007.03.011
Zelic, M. et al. RIP kinase 1–dependent endothelial necroptosis underlies systemic inflammatory response syndrome. J. Clin. Investig. 128, 2064–2075 (2018).
pubmed: 29664014
doi: 10.1172/JCI96147
pmcid: 5919800
Lee J. et al. Proteomics reveals plasma biomarkers for ischemic stroke related to the coagulation cascade. J. Mol. Neurosci. 70, 1321–1331 (2020).
Schreiber, A. et al. Necroptosis controls NET generation and mediates complement activation, endothelial damage, and autoimmune vasculitis. Proc. Natl Acad. Sci. USA 114, E9618–E9625 (2017).
pubmed: 29078325
doi: 10.1073/pnas.1708247114
pmcid: 5692554
Lusthaus, M., Mazkereth, N., Donin, N. & Fishelson, Z. Receptor-interacting protein kinases 1 and 3, and mixed lineage kinase domain-like protein are activated by sublytic complement and participate in complement-dependent cytotoxicity. Front. Immunol. 9, 306 (2018).
pubmed: 29527209
pmcid: 5829068
doi: 10.3389/fimmu.2018.00306