Myeloid-Specific Blockade of Notch Signaling by RBP-J Knockout Attenuates Spinal Cord Injury Accompanied by Compromised Inflammation Response in Mice.

Abstract

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.

• Authors: Bei-Yu Chen, Min-Hua Zheng, Yan Chen, Yan-Ling Du, Xiao-Long Sun, Xing Zhang, Li Duan, Fang Gao, Liang Liang, Hong-Yan Qin, Zhuo-Jing Luo, Hua Han
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 52 Issue 3 Pg. 1378-1390 (Dec 2015) ISSN: 1559-1182 [Electronic] United States
• PMID: 25344316 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Immunoglobulin J Recombination Signal Sequence-Binding Protein
• Nerve Tissue Proteins
• Oligopeptides
• Rbpj protein, mouse
• Receptors, Notch
• benzyloxycarbonyl-leucyl-leucyl-norleucinal
• Amyloid Precursor Protein Secretases

Topics

• Amyloid Precursor Protein Secretases (antagonists & inhibitors)
• Animals
• Cellular Microenvironment
• Cicatrix (prevention & control)
• Gene Expression Regulation (drug effects)
• Genetic Therapy
• Gliosis (prevention & control)
• Hindlimb (physiopathology)
• Immunoglobulin J Recombination Signal Sequence-Binding Protein (deficiency, genetics, physiology)
• Inflammation (physiopathology, prevention & control)
• Locomotion
• Macrophage Activation (drug effects)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Myeloid Cells (metabolism, pathology)
• Nerve Regeneration
• Nerve Tissue Proteins (deficiency, genetics, physiology)
• Oligopeptides (therapeutic use, toxicity)
• Paraplegia (etiology, physiopathology, prevention & control)
• Receptors, Notch (antagonists & inhibitors)
• Recovery of Function
• Signal Transduction (drug effects, physiology)
• Specific Pathogen-Free Organisms
• Spinal Cord Injuries (therapy)