Genetic inhibition of RIPK3 ameliorates functional outcome in controlled cortical impact independent of necroptosis
Abstract Traumatic brain injury (TBI) is a leading cause of death and disability with no specific effective therapy, in part because disease driving mechanisms remain to be elucidated. Receptor interacting protein kinases (RIPKs) are serine/threonine kinases that assemble multi-molecular complexes t...
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Nature Publishing Group
2021
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oai:doaj.org-article:c772f18f6a714ef4a0700b6cdba662be2021-11-14T12:06:44ZGenetic inhibition of RIPK3 ameliorates functional outcome in controlled cortical impact independent of necroptosis10.1038/s41419-021-04333-z2041-4889https://doaj.org/article/c772f18f6a714ef4a0700b6cdba662be2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41419-021-04333-zhttps://doaj.org/toc/2041-4889Abstract Traumatic brain injury (TBI) is a leading cause of death and disability with no specific effective therapy, in part because disease driving mechanisms remain to be elucidated. Receptor interacting protein kinases (RIPKs) are serine/threonine kinases that assemble multi-molecular complexes that induce apoptosis, necroptosis, inflammasome and nuclear factor kappa B activation. Prior studies using pharmacological inhibitors implicated necroptosis in the pathogenesis of TBI and stroke, but these studies cannot be used to conclusively demonstrate a role for necroptosis because of the possibility of off target effects. Using a model of cerebral contusion and RIPK3 and mixed lineage kinase like knockout (MLKL −/−) mice, we found evidence for activation of RIPK3 and MLKL and assembly of a RIPK1-RIPK3-MLKL necrosome complex in pericontusional brain tissue. Phosphorylated forms of RIPK3 and MLKL were detected in endothelium, CD11b + immune cells, and neurons, and RIPK3 was upregulated and activated in three-dimensional human endothelial cell cultures subjected to CCI. RIPK3 −/− and MLKL −/− mice had reduced blood-brain barrier damage at 24 h (p < 0.05), but no differences in neuronal death (6 h, p = ns in CA1, CA3 and DG), brain edema (24 h, p = ns), or lesion size (4 weeks, p = ns) after CCI. RIPK3 −/−, but not MLKL −/− mice, were protected against postinjury motor and cognitive deficits at 1–4 weeks (RIPK3 −/− vs WT: p < 0.05 for group in wire grip, Morris water maze hidden platform trials, p < 0.05 for novel object recognition test, p < 0.01 for rotarod test). RIPK3 −/− mice had reduced infiltrating leukocytes (p < 0.05 vs WT in CD11b + cells, microglia and macrophages), HMGB1 release and interleukin-1 beta activation at 24–48 h (p < 0.01) after CCI. Our data indicate that RIPK3 contributes to functional outcome after cerebral contusion by mechanisms involving inflammation but independent of necroptosis.Limin WuJoon Yong ChungTian CaoGina JinWilliam J. EdmistonSuzanne HickmanEmily S. LevyJordyn A. WhalenEliza Sophie LaRovere AbramsAlexei DegterevEng H. LoLorenzo TozziDavid L. KaplanJoseph El KhouryMichael J. WhalenNature Publishing GrouparticleCytologyQH573-671ENCell Death and Disease, Vol 12, Iss 11, Pp 1-16 (2021) |
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DOAJ |
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Cytology QH573-671 |
| spellingShingle |
Cytology QH573-671 Limin Wu Joon Yong Chung Tian Cao Gina Jin William J. Edmiston Suzanne Hickman Emily S. Levy Jordyn A. Whalen Eliza Sophie LaRovere Abrams Alexei Degterev Eng H. Lo Lorenzo Tozzi David L. Kaplan Joseph El Khoury Michael J. Whalen Genetic inhibition of RIPK3 ameliorates functional outcome in controlled cortical impact independent of necroptosis |
| description |
Abstract Traumatic brain injury (TBI) is a leading cause of death and disability with no specific effective therapy, in part because disease driving mechanisms remain to be elucidated. Receptor interacting protein kinases (RIPKs) are serine/threonine kinases that assemble multi-molecular complexes that induce apoptosis, necroptosis, inflammasome and nuclear factor kappa B activation. Prior studies using pharmacological inhibitors implicated necroptosis in the pathogenesis of TBI and stroke, but these studies cannot be used to conclusively demonstrate a role for necroptosis because of the possibility of off target effects. Using a model of cerebral contusion and RIPK3 and mixed lineage kinase like knockout (MLKL −/−) mice, we found evidence for activation of RIPK3 and MLKL and assembly of a RIPK1-RIPK3-MLKL necrosome complex in pericontusional brain tissue. Phosphorylated forms of RIPK3 and MLKL were detected in endothelium, CD11b + immune cells, and neurons, and RIPK3 was upregulated and activated in three-dimensional human endothelial cell cultures subjected to CCI. RIPK3 −/− and MLKL −/− mice had reduced blood-brain barrier damage at 24 h (p < 0.05), but no differences in neuronal death (6 h, p = ns in CA1, CA3 and DG), brain edema (24 h, p = ns), or lesion size (4 weeks, p = ns) after CCI. RIPK3 −/−, but not MLKL −/− mice, were protected against postinjury motor and cognitive deficits at 1–4 weeks (RIPK3 −/− vs WT: p < 0.05 for group in wire grip, Morris water maze hidden platform trials, p < 0.05 for novel object recognition test, p < 0.01 for rotarod test). RIPK3 −/− mice had reduced infiltrating leukocytes (p < 0.05 vs WT in CD11b + cells, microglia and macrophages), HMGB1 release and interleukin-1 beta activation at 24–48 h (p < 0.01) after CCI. Our data indicate that RIPK3 contributes to functional outcome after cerebral contusion by mechanisms involving inflammation but independent of necroptosis. |
| format |
article |
| author |
Limin Wu Joon Yong Chung Tian Cao Gina Jin William J. Edmiston Suzanne Hickman Emily S. Levy Jordyn A. Whalen Eliza Sophie LaRovere Abrams Alexei Degterev Eng H. Lo Lorenzo Tozzi David L. Kaplan Joseph El Khoury Michael J. Whalen |
| author_facet |
Limin Wu Joon Yong Chung Tian Cao Gina Jin William J. Edmiston Suzanne Hickman Emily S. Levy Jordyn A. Whalen Eliza Sophie LaRovere Abrams Alexei Degterev Eng H. Lo Lorenzo Tozzi David L. Kaplan Joseph El Khoury Michael J. Whalen |
| author_sort |
Limin Wu |
| title |
Genetic inhibition of RIPK3 ameliorates functional outcome in controlled cortical impact independent of necroptosis |
| title_short |
Genetic inhibition of RIPK3 ameliorates functional outcome in controlled cortical impact independent of necroptosis |
| title_full |
Genetic inhibition of RIPK3 ameliorates functional outcome in controlled cortical impact independent of necroptosis |
| title_fullStr |
Genetic inhibition of RIPK3 ameliorates functional outcome in controlled cortical impact independent of necroptosis |
| title_full_unstemmed |
Genetic inhibition of RIPK3 ameliorates functional outcome in controlled cortical impact independent of necroptosis |
| title_sort |
genetic inhibition of ripk3 ameliorates functional outcome in controlled cortical impact independent of necroptosis |
| publisher |
Nature Publishing Group |
| publishDate |
2021 |
| url |
https://doaj.org/article/c772f18f6a714ef4a0700b6cdba662be |
| work_keys_str_mv |
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| _version_ |
1718429488834936832 |