title: 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.affiliation: Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Chang-Le West Street #169, Xi'an, 710032, China.|Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le West Street #169, Xi'an, 710032, China.
authors.forename: Bei-Yu
authors.initials: BY
authors.lastname: Chen
authors.affiliation: Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le West Street #169, Xi'an, 710032, China. minhua_zheng@126.com.
authors.forename: Min-Hua
authors.initials: MH
authors.lastname: Zheng
authors.affiliation: Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le West Street #169, Xi'an, 710032, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le West Street #169, Xi'an, 710032, China.
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Du
authors.affiliation: Institute of Neurosciences, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Xiao-Long
authors.initials: XL
authors.lastname: Sun
authors.affiliation: Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le West Street #169, Xi'an, 710032, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Neurosciences, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Li
authors.initials: L
authors.lastname: Duan
authors.affiliation: Institute of Neurosciences, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le West Street #169, Xi'an, 710032, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liang
authors.affiliation: Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le West Street #169, Xi'an, 710032, China.
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Qin
authors.affiliation: Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Chang-Le West Street #169, Xi'an, 710032, China. zjluo@fmmu.edu.cn.
authors.forename: Zhuo-Jing
authors.initials: ZJ
authors.lastname: Luo
authors.affiliation: Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le West Street #169, Xi'an, 710032, China. huahan@fmmu.edu.cn.
authors.forename: Hua
authors.initials: H
authors.lastname: Han
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D060833:Cellular Microenvironment; D002921:Cicatrix / Q000517:prevention & control; D005786:Gene Expression Regulation / Q000187:drug effects; D015316:Genetic Therapy; D005911:Gliosis / Q000517:prevention & control; D006614:Hindlimb / Q000503:physiopathology; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D007249:Inflammation / Q000503:physiopathology / Q000517:prevention & control*; D008124:Locomotion; D008262:Macrophage Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology*; D009416:Nerve Regeneration; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D009842:Oligopeptides / Q000627:therapeutic use / Q000633:toxicity; D010264:Paraplegia / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D051880:Receptors, Notch / Q000037:antagonists & inhibitors*; D020127:Recovery of Function; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013047:Specific Pathogen-Free Organisms; D013119:Spinal Cord Injuries / Q000628:therapy*
chemical_list: D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D009419:Nerve Tissue Proteins; D009842:Oligopeptides; C497571:Rbpj protein, mouse; D051880:Receptors, Notch; C523462:benzyloxycarbonyl-leucyl-leucyl-norleucinal; D053829:Amyloid Precursor Protein Secretases
keywords: GSI; Macrophages; Notch signaling; RBP-J; Spinal cord injury