title: Myelin activates FAK/Akt/NF-kappaB pathways and provokes CR3-dependent inflammatory response in murine system.
abstract: Inflammatory response following central nervous system (CNS) injury contributes to progressive neuropathology and reduction in functional recovery. Axons are sensitive to mechanical injury and toxic inflammatory mediators, which may lead to demyelination. Although it is well documented that degenerated myelin triggers undesirable inflammatory responses in autoimmune diseases such as multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), there has been very little study of the direct inflammatory consequences of damaged myelin in spinal cord injury (SCI), i.e., there is no direct evidence to show that myelin debris from injured spinal cord can trigger undesirable inflammation in vitro and in vivo. Our data showed that myelin can initiate inflammatory responses in vivo, which is complement receptor 3 (CR3)-dependent via stimulating macrophages to express pro-inflammatory molecules and down-regulates expression of anti-inflammatory cytokines. Mechanism study revealed that myelin-increased cytokine expression is through activation of FAK/PI3K/Akt/NF-kappaB signaling pathways and CR3 contributes to myelin-induced PI3K/Akt/NF-kappaB activation and cytokine production. The myelin induced inflammatory response is myelin specific as sphingomyelin (the major lipid of myelin) and myelin basic protein (MBP, one of the major proteins of myelin) are not able to activate NF-kappaB signaling pathway. In conclusion, our results demonstrate a crucial role of myelin as an endogenous inflammatory stimulus that induces pro-inflammatory responses and suggest that blocking myelin-CR3 interaction and enhancing myelin debris clearance may be effective interventions for treating SCI.
authors.affiliation: W. M. Keck Center for Collaborative Neuroscience, Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Sun
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.forename: Tianxiang
authors.initials: T
authors.lastname: Chen
authors.forename: Tianyi
authors.initials: T
authors.lastname: Li
authors.forename: Kai
authors.initials: K
authors.lastname: Cao
authors.forename: Andrew
authors.initials: A
authors.lastname: Lu
authors.forename: Yongxiong
authors.initials: Y
authors.lastname: Chen
authors.forename: Dongming
authors.initials: D
authors.lastname: Sun
authors.forename: Jianhong
authors.initials: J
authors.lastname: Luo
authors.forename: Jianqing
authors.initials: J
authors.lastname: Fan
authors.forename: Wise
authors.initials: W
authors.lastname: Young
authors.forename: Yi
authors.initials: Y
authors.lastname: Ren
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D016207:Cytokines; D018836:Inflammation Mediators; D016177:Macrophage-1 Antigen; D016328:NF-kappa B; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt