title: PI3Kγ inhibition alleviates symptoms and increases axon number in experimental autoimmune encephalomyelitis mice.
abstract: Phosphoinositide 3-kinase γ (PI3Kγ) is a shared downstream component of chemokine-mediated signaling pathways and regulates migration, proliferation and activation of inflammatory cells. PI3Kγ has been shown to play a crucial role in regulating inflammatory responses during the progression of several diseases. We investigated the potential function of PI3Kγ in mediating inflammatory reactions and the development of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). We found that systemic treatment with selective PI3Kγ inhibitor AS-604850 significantly reduced the number of infiltrated leukocytes in the CNS and ameliorated the clinical symptoms of EAE mice. Treatment with this PI3Kγ inhibitor enhanced myelination and axon number in the spinal cord of EAE mice. Consistently, we demonstrated that PI3Kγ deletion in knockout mice mitigates the clinical sign of EAE compared to PI3Kγ+/+ controls. PI3Kγ deletion increased the number of axons in the lumbar spinal cord, including descending 5-HT-positive serotonergic fiber tracts. Our results indicate that PI3Kγ contributes to development of autoimmune CNS inflammation and that PI3Kγ blockade may provide a great potential for treating patients with MS.
authors.affiliation: Shriners Hospitals Pediatric Research Center, Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.forename: D
authors.initials: D
authors.lastname: Park
authors.forename: P M Abdul
authors.initials: PMA
authors.lastname: Muneer
authors.forename: B
authors.initials: B
authors.lastname: Xu
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: B
authors.initials: B
authors.lastname: Xing
authors.forename: D
authors.initials: D
authors.lastname: Wu
authors.forename: S
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000473:pathology; D017252:CD3 Complex / Q000378:metabolism; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000172:deficiency / Q000378:metabolism*; D004149:Dioxoles / Q000737:chemistry / Q000627:therapeutic use*; D004195:Disease Models, Animal; D053331:Ectodysplasins / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D016900:Neurofilament Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012701:Serotonin / Q000378:metabolism; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology*; D045162:Thiazolidinediones / Q000737:chemistry / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: C505145:5-(2,2-difluorobenzo(1,3)dioxol-5-ylmethylene)thiazolidine-2,4-dione; D017252:CD3 Complex; D004149:Dioxoles; D053331:Ectodysplasins; C506019:Eda protein, mouse; D004791:Enzyme Inhibitors; D063308:Myelin-Oligodendrocyte Glycoprotein; D016900:Neurofilament Proteins; D010446:Peptide Fragments; D000081082:Phosphoinositide-3 Kinase Inhibitors; D045162:Thiazolidinediones; C517781:myelin oligodendrocyte glycoprotein (34-56); C051774:neurofilament protein H; D012701:Serotonin; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse
keywords: DMSO; EAE; GPCR; GTP-binding protein-coupled receptor; KO; LFB; Luxol fast blue; MBP; MOG; MS; NF; PBS; PI(3 4 5)P3; PI(4 5)P2; PI3 kinase γ; PI3Kγ; Phosphate-buffered saline; axon; dimethyl sulfoxide; experimental autoimmune encephalomyelitis; functional recovery; knockout; multiple sclerosis; myelin basic protein; myelin oligodendrocyte glycoprotein; myelination; neurofilament; phosphatidylinositol-3 4 5-trisphosphate; phosphatidylinositol-4 5-bisphosphate; phosphoinositide 3-kinase γ