Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis.
Neuroinflammatory diseases, such as multiple sclerosis (MS), result from aberrant leukocyte traffic into the central nervous system (CNS). To breach the specialized blood-brain barrier, activated leukocytes interact with CNS endothelial cells (EC) and activate a CD54-mediated signaling pathway controlling the Rho GTPase. To function correctly Rho requires posttranslational prenylation, and this can be inhibited by depleting the supply of isoprenoids through inhibition of the cholesterol synthesis pathway with 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase) inhibitors (statins). Here we show that treatment of brain EC in vitro with lovastatin inhibits Rho-mediated transendothelial T cell migration. This effect can be reversed by supplementation with mevalonolactone, the downstream product of HMG-CoA reductase, or by ectopic expression of myristoylated Rho, which remains active in the absence of prenylation. In a relapsing-remitting mouse model of MS, lovastatin treatment inhibited leukocyte migration into the CNS and significantly attenuated the development of both acute and relapsing clinical disease. These studies demonstrate that the indirect pharmacological inhibition of Rho proteins in brain EC by statins can inhibit a key stage in the pathogenesis of neuroinflammation, namely leukocyte migration across the blood-brain barrier. These studies demonstrate a novel effect of statins in modulating the immune response in neuroinflammtory diseases and may provide additional rationale for their use in the treatment of MS.
Greenwood
John
J
Division of Cell Biology, Institute of Ophthalmology, University College London, Bath Street, London, EC1V 9EL, UK.
Walters
Claire E
CE
Division of Cell Biology, Institute of Ophthalmology, University College London, Bath Street, London, EC1V 9EL, UK.
Pryce
Gareth
G
Department of Neuroinflammation, Institute of Neurology, University College London, 1 Wakefield Street London, WC1N 1PJ, UK.
Kanuga
Naheed
N
Division of Cell Biology, Institute of Ophthalmology, University College London, Bath Street, London, EC1V 9EL, UK.
Beraud
Evelyne
E
Laboratoire d'Immunologie, Faculté de Medécine, Universite de la Méditerranée, Marseille, France.
Baker
David
D
Department of Neuroinflammation, Institute of Neurology, University College London, 1 Wakefield Street London, WC1N 1PJ, UK.
Adamson
Peter
P
Division of Cell Biology, Institute of Ophthalmology, University College London, Bath Street, London, EC1V 9EL, UK.
D000818:Animals; D001921:Brain / Q000098:blood supply; D002465:Cell Movement / Q000187:drug effects; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology*; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D012074:Remission Induction; D055502:Secondary Prevention; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D020741:rho GTP-Binding Proteins