title: Suppression of inflammatory responses during myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis is regulated by AKT3 signaling.
abstract: AKT3, a member of the serine/threonine kinase AKT family, is involved in a variety of biologic processes. AKT3 is expressed in immune cells and is the major AKT isoform in the CNS representing 30% of the total AKT expressed in spinal cord, and 50% in the brain. Myelin-oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) is a mouse model in which lymphocytes and monocytes enter the CNS, resulting in inflammation, demyelination, and axonal injury. We hypothesized that during EAE, deletion of AKT3 would negatively affect the CNS of AKT3(-/-) mice, making them more susceptible to CNS damage. During acute EAE, AKT3(-/-)mice were more severely affected than wild type (WT) mice. Evaluation of spinal cords showed that during acute and chronic disease, AKT3(-/-) spinal cords had more demyelination compared with WT spinal cords. Quantitative RT-PCR determined higher levels of IL-2, IL-17, and IFN-γ mRNA in spinal cords from AKT3(-/-) mice than WT. Experiments using bone marrow chimeras demonstrated that AKT3(-/-) mice receiving AKT3-deficient bone marrow cells had elevated clinical scores relative to control WT mice reconstituted with WT cells, indicating that altered function of both CNS cells and bone marrow-derived immune cells contributed to the phenotype. Immunohistochemical analysis revealed decreased numbers of Foxp3(+) regulatory T cells in the spinal cord of AKT3(-/-) mice compared with WT mice, whereas in vitro suppression assays showed that AKT3-deficient Th cells were less susceptible to regulatory T cell-mediated suppression than their WT counterparts. These results indicate that AKT3 signaling contributes to the protection of mice against EAE.
authors: Department of Pathology, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY 10461, USA.
authors: Vladislav
authors: V
authors: Tsiperson
authors: Ross C
authors: RC
authors: Gruber
authors: Michael F
authors: MF
authors: Goldberg
authors: Ayana
authors: A
authors: Jordan
authors: Jason G
authors: JG
authors: Weinger
authors: Fernando
authors: F
authors: Macian
authors: Bridget
authors: B
authors: Shafit-Zagardo
mesh_terms: D000208:Acute Disease; D000818:Animals; D002908:Chronic Disease; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control*; D020022:Genetic Predisposition to Disease; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology*; D008161:Lumbosacral Region; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000502:physiology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D018836:Inflammation Mediators; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); C491753:Akt3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt