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PMID: 16478881 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Rho-mediated regulation of tight junctions during monocyte migration across the blood-brain barrier in HIV-1 encephalitis (HIVE).

Blood ·Vol. 107 ·No. 12 ·2006-06-15 ·Pages 4770-80

Persidsky Y, Heilman D, Haorah J, Zelivyanskaya M, Persidsky R, Weber GA, Shimokawa H, Kaibuchi K, Ikezu T

Abstract

The blood-brain barrier (BBB) is compromised during progressive HIV-1 infection, but how this occurs is incompletely understood. We studied the integrity of tight junctions (TJs) of brain microvascular endothelial cells (BMVECs) in an in vitro BBB system and in human brain tissues with HIV-1 encephalitis (HIVE). A downregulation of TJ proteins, claudin-5 and occludin, paralleled monocyte migration into the brain during HIVE. Because small G proteins (such as Rho) can play a role in BMVEC TJ assembly, an artificial BBB system explored the relationship among TJs, Rho/Rho kinase (RhoK) activation, and transendothelial monocyte migration. Coculture of monocytes with endothelial cells led to Rho activation and phosphorylation of TJ proteins. Rho and RhoK inhibitors blocked migration of infected and uninfected monocytes. The RhoK inhibitor protected BBB integrity and reversed occludin/claudin-5 phosphorylation associated with monocyte migration. BMVEC transfection with a constitutively active mutant of RhoK led to dislocation of occludin from the membrane and loss of BMVEC cell contacts. When dominant-negative RhoK-transfected BMVECs were used in BBB constructs, monocyte migration was reduced by 84%. Thus, loss of TJ integrity was associated with Rho activation caused by monocyte brain migration, suggesting that Rho/RhoK activation in BMVECs could be an underlying cause of BBB impairment during HIVE.

MeSH Terms
Blood-Brain Barrier/immunology,virology Cell Movement/drug effects,genetics,immunology Cells, Cultured Claudin-5 Down-Regulation/drug effects,genetics,immunology Encephalitis, Viral/genetics,immunology,virology Enzyme Activation/drug effects,genetics,immunology G-Protein-Coupled Receptor Kinase 1/antagonists & inhibitors,genetics,immunology HIV Infections/genetics,immunology,virology HIV-1/immunology Humans Membrane Proteins/immunology Monocytes/immunology,virology Mutation/immunology Occludin Protein Kinase Inhibitors/pharmacology Protein Transport/genetics,immunology Tight Junctions/genetics,immunology Transfection
Chemicals
CLDN5 protein, human Claudin-5 Membrane Proteins OCLN protein, human Occludin Protein Kinase Inhibitors G-Protein-Coupled Receptor Kinase 1 GRK1 protein, human
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Persidsky Yuri
Center for Neurovirology and Neurodegenerative Disorders, Nebraska Medical Center, Omaha, NE 68198-5215, USA. ypersids@unmc.edu
Heilman David
Haorah James
Zelivyanskaya Marina
Persidsky Raisa
Weber Gregory A
Shimokawa Hiroaki
Kaibuchi Kozo
Ikezu Tsuneya
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
0006-4971
DOI
10.1182/blood-2005-11-4721
Email
ypersids@unmc.edu
Published
2006-06-15
Epub
2006-00-14
Pages
4770-80
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC1895810
Subset
IM
Grants
NIAAA NIH HHS · R37 AA015913 · United States
NINDS NIH HHS · P01 NS043985 · United States
NIAAA NIH HHS · R01 AA015913 · United States
NIMH NIH HHS · R01 MH072539 · United States
NIMH NIH HHS · R01 MH65151 · United States
External Links
PubMed source DOI: 10.1182/blood-2005-11-4721 PMC Full Text View journal details
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