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Cited by 200Barrier Structure and Function StudiesHIV Research and TreatmentCell Adhesion Molecules Research

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

Open access
Persidsky, Yuri, Heilman, David, Haorah, James, Zelivyanskaya, Marina, Persidsky, Raisa, Weber, Gregory A., Shimokawa, Hiroaki, Kaibuchi, Kozo +1 more·2006·Blood
DOI 10.1182/blood-2005-11-4721PMC PMC1895810
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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.

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Crossref · 10.1182/blood-2005-11-4721

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  • In HIV-1-associated dementia or HIV encephalitis, post mortem brain tissue studies report microvascular degeneration and blood-brain barrier breakdown including reduced pericyte coverage, reduced and disrupted tight junctions, capillary basement membrane changes, perivascular macrophage infiltration, and reduced brain endothelial ABCB1 (P-gp) expression.

    “Post mortem brain tissue studies in HAD or HIV encephalitis report microvascular degeneration and BBB breakdown including reduced pericyte coverage (439), reduced and disrupted TJs (471, 664), capillary basement membrane changes (471), perivascular macrophage infiltration (471), and reduced brain endothelial ABCB1 (P-gp) expression (346).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [471]

    The Results (page unavailable) report reduced and disrupted occludin and claudin-5 staining in HIVE microvessels alongside monocyte infiltration; the Introduction also describes perivascular macrophage accumulation and BBB compromise. Our copy does not report capillary basement membrane changes, although the citing sentence assigns that finding to this source. Reduced pericyte coverage and ABCB1 expression have different citations in the sentence and are not assessed here. (LLM, conf=0.87)

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Research works printed but not linked: 1

  1. [57]Wojciak-Stothard B, Entwistle A, Garg R, Ridley AJ. Regulation of TNF-alpha-induced reorganization of the actin cytoskeleton and cell-cell junctions by Rho, Rac, and Cdc42 in human endothelial cells. J Cell Physiol. 1998;176: 150-165. [DOI] [PubMed] [Google Scholar]

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Authors
Persidsky, Y., Heilman, D., Haorah, J., Zelivyanskaya, M., Persidsky, R., Weber, G. A., Shimokawa, H., Kaibuchi, K., & Ikezu, T.
Affiliations
University of Nebraska Medical Center (US)
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2006-06-15
Volume
107
Issue
12
Pages
4770-4780
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood-2005-11-4721
PMC
PMC1895810
OpenAlex
W2094716188
Cited by
200
References
74
Citations by year
2026: 2 · 2025: 4 · 2024: 7 · 2023: 6 · 2022: 4 · 2021: 7 · 2020: 11 · 2019: 6 · 2018: 10 · 2017: 6 · 2016: 13 · 2015: 13 · 2014: 11 · 2013: 8 · 2012: 17
FWCI
10.30
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • University of Arizona
  • National Institute on Alcohol Abuse and Alcoholism (R37AA015913, R01AA015913)
  • National Institute of Mental Health (R01MH072539, R01MH065151, R01-MH65151)
  • National Institute of Neurological Disorders and Stroke (P01NS043985)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
Keywords
HIV-1 encephalitis, blood-brain barrier, tight junctions, Rho kinase, Rho activation, monocyte migration, brain microvascular endothelial cells, claudin-5, occludin, blood-brain barrier integrity
MeSH terms
Blood-Brain Barrier, Cell Movement, Cells, Cultured, Enzyme Activation, Humans, Membrane Proteins, Monocytes, Mutation, Transfection, HIV-1, Down-Regulation, HIV Infections, Encephalitis, Viral, Tight Junctions, Protein Transport, Protein Kinase Inhibitors, G-Protein-Coupled Receptor Kinase 1, Claudin-5, Occludin

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