title: Phospholipase D1 mediates lymphocyte adhesion and migration in experimental autoimmune encephalomyelitis.
abstract: Lymphocyte adhesion and subsequent trafficking across endothelial barriers are essential steps in various immune-mediated disorders of the CNS, including MS. The molecular mechanisms underlying these processes, however, are still unknown. Phospholipase D1 (PLD1), an enzyme that generates phosphatidic acid through hydrolysis of phosphatidylcholine and additionally yields choline as a product, has been described as regulator of the cell mobility. By using PLD1-deficient mice, we investigated the functional significance of PLD1 for lymphocyte adhesion and migration in vitro and after myelin oligodendrocyte glycoprotein (MOG)35-55 -induced EAE, a model of human MS. The lack of PLD1 reduced chemokine-mediated static adhesion of lymphocytes to the endothelial adhesion molecules vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) in vitro, and was accompanied by a decreased migratory capacity in both blood brain barrier and cell migration models. Importantly, PLD1 is also relevant for the recruitment of immune cells into the CNS in vivo since disease severity after EAE was significantly attenuated in PLD1-deficient mice. Furthermore, PLD1 expression could be detected on lymphocytes in MS patients. Our findings suggest a critical function of PLD1-dependent intracellular signaling cascades in regulating lymphocyte trafficking during autoimmune CNS inflammation.
authors.affiliation: Department of Neurology, University of Muenster, Muenster, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Göbel
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schuhmann
authors.forename: Susann
authors.initials: S
authors.lastname: Pankratz
authors.forename: David
authors.initials: D
authors.lastname: Stegner
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Herrmann
authors.forename: Attila
authors.initials: A
authors.lastname: Braun
authors.forename: Johanna
authors.initials: J
authors.lastname: Breuer
authors.forename: Stefan
authors.initials: S
authors.lastname: Bittner
authors.forename: Tobias
authors.initials: T
authors.lastname: Ruck
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology; D002448:Cell Adhesion / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D042783:Endothelial Cells / Q000276:immunology; D005260:Female; D007249:Inflammation / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D010739:Phospholipase D / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology
chemical_list: D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D010739:Phospholipase D; C106801:phospholipase D1
keywords: Central nervous system inflammation; Experimental autoimmune encephalomyelitis; Lymphocyte migration; Multiple sclerosis; Phospholipase D1 (PLD1)