Cell-specific activation of RIPK1 and MLKL after intracerebral hemorrhage in mice
| Autor: | Joon Yong Chung, Tanya Songtachalert, Alexei Degterev, David L. Kaplan, Gina Jin, Aliyah Sarro-Schwartz, Neil D. Fernandes, Michael J. Whalen, William J Edmiston, Saef Izzy, Siddharth Balachandran, So Hee Ahn, Sevda Lule, Eng H. Lo, Limin Wu |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Cell type Programmed cell death Cell Membrane Permeability Endothelium Necroptosis Inflammation Pharmacology Pathogenesis Mice Necrosis 03 medical and health sciences RIPK1 0302 clinical medicine medicine Animals Edema Cerebral Hemorrhage 030304 developmental biology Mice Knockout Neurons 0303 health sciences Behavior Animal Kinase business.industry Original Articles medicine.anatomical_structure Neurology Blood-Brain Barrier Receptor-Interacting Protein Serine-Threonine Kinases Neurology (clinical) medicine.symptom Cardiology and Cardiovascular Medicine business Protein Kinases 030217 neurology & neurosurgery |
| Zdroj: | J Cereb Blood Flow Metab |
| ISSN: | 1559-7016 0271-678X |
| DOI: | 10.1177/0271678x20973609 |
| Popis: | Receptor-interacting protein kinase-1 (RIPK1) is a master regulator of cell death and inflammation, and mediates programmed necrosis (necroptosis) via mixed-lineage kinase like (MLKL) protein. Prior studies in experimental intracerebral hemorrhage (ICH) implicated RIPK1 in the pathogenesis of neuronal death and cognitive outcome, but the relevant cell types involved and potential role of necroptosis remain unexplored. In mice subjected to autologous blood ICH, early RIPK1 activation was observed in neurons, endothelium and pericytes, but not in astrocytes. MLKL activation was detected in astrocytes and neurons but not endothelium or pericytes. Compared with WT controls, RIPK1 kinase-dead ( RIPK1D138N/D138N) mice had reduced brain edema (24 h) and blood-brain barrier (BBB) permeability (24 h, 30 d), and improved postinjury rotarod performance. Mice deficient in MLKL ( Mlkl-/-) had reduced neuronal death (24 h) and BBB permeability at 24 h but not 30d, and improved post-injury rotarod performance vs. WT. The data support a central role for RIPK1 in the pathogenesis of ICH, including cell death, edema, BBB permeability, and motor deficits. These effects may be mediated in part through the activation of MLKL-dependent necroptosis in neurons. The data support development of RIPK1 kinase inhibitors as therapeutic agents for human ICH. |
| Databáze: | OpenAIRE |
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