title: Neuronal I kappa B kinase beta protects mice from autoimmune encephalomyelitis by mediating neuroprotective and immunosuppressive effects in the central nervous system.
abstract: Some aspects of CNS-directed autoimmunity in multiple sclerosis are modeled in mice by immunization with myelin Ags where tissue damage is driven by myelin-reactive Th1 and Th17 effector lymphocytes. Whether the CNS plays an active role in controlling such autoimmune diseases is unknown. We used mice in which IkappaB kinase beta was deleted from Ca(2+)/calmodulin-dependent kinase IIalpha-expressing neurons (nIKKbetaKO) to investigate the contribution of neuronal NF-kappaB to the development of myelin oligodendrocyte glycoprotein 35-55-induced experimental autoimmune encephalomyelitis. We show that nIKKbetaKO mice developed a severe, nonresolving disease with increased axon loss compared with controls and this was associated with significantly reduced CNS production of neuroprotective factors (vascular endothelial growth factor, CSF1-R, and FLIP) and increased production of proinflammatory cytokines (IL-6, TNF, IL-12, IL-17, and CD30L) and chemokines. The isolation of CNS-infiltrating monocytes revealed greater numbers of CD4(+) T cells, reduced numbers of NK1.1(+) cells, and a selective accumulation of Th1 cells in nIKKbetaKO CNS from early in the disease. Our results show that neurons play an important role in determining the quality and outcome of CNS immune responses, specifically that neuronal IkappaB kinase beta is required for neuroprotection, suppression of inflammation, limitation of Th1 lymphocyte accumulation, and enhancement of NK cell recruitment in experimental autoimmune encephalomyelitis-affected CNS and stress the importance of neuroprotective strategies for the treatment of multiple sclerosis.
authors.affiliation: Laboratory of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece.
authors.forename: Mary
authors.initials: M
authors.lastname: Emmanouil
authors.forename: Era
authors.initials: E
authors.lastname: Taoufik
authors.forename: Vivian
authors.initials: V
authors.lastname: Tseveleki
authors.forename: Sotiris-Spyros
authors.initials: SS
authors.lastname: Vamvakas
authors.forename: Theodore
authors.initials: T
authors.lastname: Tselios
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Hans
authors.initials: H
authors.lastname: Lassmann
authors.forename: Lesley
authors.initials: L
authors.lastname: Probert
mesh_terms: D000818:Animals; D001369:Axons / Q000276:immunology / Q000473:pathology; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002464:Cell Migration Inhibition / Q000235:genetics / Q000276:immunology; D002490:Central Nervous System / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D002908:Chronic Disease; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007166:Immunosuppressive Agents / Q000378:metabolism* / Q000494:pharmacology; D018836:Inflammation Mediators / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology
chemical_list: D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D051550:I-kappa B Kinase