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Tight Junction Regulation by Morphine and HIV-1 Tat Modulates Blood–Brain Barrier Permeability

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Abstract

Human immunodeficiency virus (HIV)-1 patients who abuse opiates are at a greater risk of developing neurological complications of AIDS. Alterations in blood–brain barrier (BBB) integrity are associated with cytoskeletal disorganization and disruption of tight junction (TJ) integrity. We hypothesize that opiates in combination with HIV-1 viral proteins can modulate TJ expression in primary brain microvascular endothelial cells (BMVEC), thereby compromising BBB integrity and exacerbating HIV-1 neuropathogenesis. We investigated the effect of morphine and/or tat on the expression of TJ proteins ZO-1, JAM-2, Occludin and P-glycoprotein and the functional effects of TJ modulation in BMVEC. Morphine and/or tat, via the activation of pro-inflammatory cytokines, intracellular Ca2+ release, and activation of myosin light chain kinase, modulated TJ expression resulting in decreased transendothelial electric resistance and enhanced transendothelial migration across the BBB. These studies may lead to the development of novel anti-HIV-1 therapeutics that target specific TJ proteins, thus preventing TJ disruption in opiate using HIV-1 patients.

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Acknowledgments

This work was supported in part by grants from the Margaret Duffy and Robert Cameron Troup Memorial Fund of Kaleida Health and the Kaleida Health Foundation. Authors would like to thank Elizabeth Hemedinger, Manager of Laboratory Services at Upstate New York Transplant Services, 110 Broadway, Buffalo, NY 14203 for her assistance in providing leukocyte depletion filters as source of peripheral leukocyte populations for these studies.

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Authors and Affiliations

  1. Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Buffalo General Hospital, 301 Multi Research Bldg, 100 High Street, Buffalo, NY, 14203, USA

    Supriya D. Mahajan, Ravikumar Aalinkeel, Donald E. Sykes, Jessica L. Reynolds, B. Bindukumar, Ramnik Chawda & Stanley A. Schwartz

  2. Department of Pharmacology, School of Medicine and Biomedical Sciences, Buffalo, NY, 14260, USA

    Stanley F. Fernandez

  3. Upstate New York Transplant Services, 110 Broadway, Buffalo, NY, 14203, USA

    Thomas C. Shanahan

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  1. Supriya D. Mahajan
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  2. Ravikumar Aalinkeel
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  3. Donald E. Sykes
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  4. Jessica L. Reynolds
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  5. B. Bindukumar
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  6. Stanley F. Fernandez
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Corresponding author

Correspondence to Stanley A. Schwartz.

Appendix: Abbreviations

Appendix: Abbreviations

HIV-1:

human immunodeficiency virus-1

ADC:

AIDS dementia complex

BBB:

blood–brain barrier

BMVEC:

brain microvascular endothelial cells

CNS:

central nervous system

DEPC:

diethyl pyrocarbonate

HAD:

HIV-1-associated dementia

HIVE:

human immunodeficiency virus associated encephalopathy

IL-8:

Interleukin-8

JAM-2:

junctional adhesion molecule-2

MLCK:

myosin light chain kinase

NHA:

normal human astrocytes

PBS:

phosphate buffer saline

TAI:

transcript accumulation index

TEER:

transendothelial electrical resistance

TJ:

tight junctions

TNF-α:

tumor necrosis factor-alpha

ZO-1:

zona occludins

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Mahajan, S.D., Aalinkeel, R., Sykes, D.E. et al. Tight Junction Regulation by Morphine and HIV-1 Tat Modulates Blood–Brain Barrier Permeability. J Clin Immunol 28, 528–541 (2008). https://doi.org/10.1007/s10875-008-9208-1

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