Myeloid-Specific Blockade of Notch Signaling by RBP-J Knockout Attenuates Spinal Cord Injury Accompanied by Compromised Inflammation Response in Mice
| Autor: | Yan-Ling Du, Hua Han, Min-Hua Zheng, Xing Zhang, Bei-Yu Chen, Li Duan, Liang Liang, Xiao-Long Sun, Yan Chen, Hong-Yan Qin, Zhuo-Jing Luo, Fang Gao |
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| Rok vydání: | 2014 |
| Předmět: |
Myeloid
Neuroscience (miscellaneous) Notch signaling pathway Mice Transgenic Nerve Tissue Proteins Inflammation Biology Glial scar Cicatrix Mice Cellular and Molecular Neuroscience medicine Animals Myeloid Cells Gliosis Axon Receptor Transcription factor Protein kinase B Spinal Cord Injuries Mice Knockout Paraplegia Receptors Notch Genetic Therapy Recovery of Function Macrophage Activation Hindlimb Nerve Regeneration Specific Pathogen-Free Organisms Mice Inbred C57BL medicine.anatomical_structure Cellular Microenvironment Gene Expression Regulation Neurology Immunoglobulin J Recombination Signal Sequence-Binding Protein Immunology Cancer research Amyloid Precursor Protein Secretases medicine.symptom Oligopeptides Locomotion Signal Transduction |
| Zdroj: | Molecular Neurobiology. 52:1378-1390 |
| ISSN: | 1559-1182 0893-7648 |
| DOI: | 10.1007/s12035-014-8934-z |
| Popis: | The outcome of spinal cord injury (SCI) is determined by both neural cell-intrinsic survival pathways and tissue microenvironment-derived signals. Macrophages dominating the inflammatory responses in SCI possess both destructive and reparative potentials, according to their activation status. Notch signaling is involved in both cell survival and macrophage-mediated inflammation, but a comprehensive role of Notch signaling in SCI has been elusive. In this study, we compared the effects of general Notch blockade by a pharmaceutical γ-secretase inhibitor (GSI) and myeloid-specific Notch signal disruption by recombination signal binding protein Jκ (RBP-J) knockout on SCI. The administration of Notch signal inhibitor GSI resulted in worsened hind limb locomotion and exacerbated inflammation. However, mice lacking RBP-J, the critical transcription factor mediating signals from all four mammalian Notch receptors, in myeloid lineage displayed promoted functional recovery, attenuated glial scar formation, improved neuronal survival and axon regrowth, and mitigated inflammatory response after SCI. These benefits were accompanied by enhanced AKT activation in the lesion area after SCI. These findings demonstrate that abrogating Notch signal in myeloid cells ameliorates inflammation response post-SCI and promotes functional recovery, but general pharmaceutical Notch interception has opposite effects. Therefore, clinical intervention of Notch signaling in SCI needs to pinpoint myeloid lineage to avoid the counteractive effects of global inhibition. |
| Databáze: | OpenAIRE |
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