Human blood-brain barrier disruption by retroviral-infected lymphocytes: role of myosin light chain kinase in endothelial tight-junction disorganization.
The blood-brain barrier (BBB), which constitutes the interface between blood and cerebral parenchyma, has been shown to be disrupted during retroviral associated neuromyelopathies. Human T cell leukemia virus (HTLV-1)-associated myelopathy/tropical spastic paraparesis is a slowly progressive neurodegenerative disease, in which evidence of BBB breakdown has been demonstrated by the presence of lymphocytic infiltrates in the CNS and plasma protein leakage through cerebral endothelium. Using an in vitro human BBB model, we investigated the cellular and molecular mechanisms involved in endothelial changes induced by HTLV-1-infected lymphocytes. We demonstrate that coculture with infected lymphocytes induces an increase in paracellular endothelial permeability and transcellular migration, via IL-1alpha and TNF-alpha secretion. This disruption is associated with tight junction disorganization between endothelial cells, and alterations in the expression pattern of tight junction proteins such as zonula occludens 1. These changes could be prevented by inhibition of the NF-kappaB pathway or of myosin light chain kinase activity. Such disorganization was confirmed in histological sections of spinal cord from an HTLV-1-associated myelopathy/tropical spastic paraparesis patient. Based on this BBB model, the present data indicate that HTLV-1-infected lymphocytes can induce BBB breakdown and may be responsible for the CNS infiltration that occurs in the early steps of retroviral-associated neuromyelopathies.
Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Département de Virologie and Centre National de la Recherche Scientifique Unité de Recherche Associée 3015, Institut Pasteur, Paris, France.
Philippe Vicente
PV
Afonso
Simona
S
Ozden
Marie-Christine
MC
Prevost
Christine
C
Schmitt
Danielle
D
Seilhean
Babette
B
Weksler
Pierre-Olivier
PO
Couraud
Antoine
A
Gessain
Ignacio Andres
IA
Romero
Pierre-Emmanuel
PE
Ceccaldi
D001812:Blood-Brain Barrier / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000648:ultrastructure / Q000821:virology; D002461:Cell Line, Transformed; D002531:Cerebellum / Q000098:blood supply / Q000201:enzymology / Q000276:immunology / Q000648:ultrastructure; D042783:Endothelial Cells / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000821:virology; D004730:Endothelium, Vascular / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000821:virology; D015368:Human T-lymphotropic virus 1 / Q000276:immunology*; D006801:Humans; D053582:Interleukin-1alpha / Q000276:immunology / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure / Q000821:virology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000276:immunology; D018448:Models, Immunological; D009219:Myosin-Light-Chain Kinase / Q000276:immunology* / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015493:Paraparesis, Tropical Spastic / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000821:virology; D010750:Phosphoproteins / Q000096:biosynthesis / Q000276:immunology; D013116:Spinal Cord / Q000201:enzymology / Q000276:immunology / Q000648:ultrastructure / Q000821:virology; D019108:Tight Junctions / Q000276:immunology* / Q000378:metabolism / Q000648:ultrastructure; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D062826:Zonula Occludens-1 Protein
D053582:Interleukin-1alpha; D008565:Membrane Proteins; D010750:Phosphoproteins; C569042:TJP1 protein, human; D014409:Tumor Necrosis Factor-alpha; D062826:Zonula Occludens-1 Protein; D009219:Myosin-Light-Chain Kinase