Cocaine-mediated alteration in tight junction protein expression and modulation of CCL2/CCR2 axis across the blood-brain barrier: implications for HIV-dementia.
One of the hallmark features underlying the pathogenesis of HIV encephalitis is the disruption of blood-brain barrier (BBB). Cocaine, often abused by HIV-infected patients, has been suggested to worsen the HIV-associated dementia (HAD) via unknown mechanisms. The objective of the present study was to explore the effects of cocaine on BBB permeability using human brain microvascular endothelial cells (HBMECs). Additionally, because the chemokine CCL2 and its receptor CCR2 play a crucial role in the recruitment of inflammatory cells into the central nervous system in HAD brains, we tested for the effect of cocaine in modulating the CCL2/CCR2 axis. Our findings suggest that exposure of HBMECs to cocaine correlated with the breakdown of ZO-1 tight junction protein and reorganization of the cytoskeleton resulting in stress fiber formation. Furthermore, cocaine also modulated upregulation of the CCL2/CCR2 axis in monocytes. These findings conform to the multifaceted effects of cocaine leading to accelerated progression of HIV-1 neuropathogenesis.
Department of Molecular & Integrative Physiology, University of Kansas Medical Center, 5000 Wahl Hall East, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.
Navneet K
NK
Dhillon
Fuwang
F
Peng
Sirosh
S
Bokhari
Shannon
S
Callen
Sun-Hye
SH
Shin
Xuhui
X
Zhu
Kee-Jun
KJ
Kim
Shilpa J
SJ
Buch
D015526:AIDS Dementia Complex / Q000503:physiopathology*; D001812:Blood-Brain Barrier / Q000187:drug effects*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000187:drug effects*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000096:biosynthesis / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010750:Phosphoproteins / Q000096:biosynthesis / Q000187:drug effects; D054390:Receptors, CCR2 / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D022502:Stress Fibers / Q000187:drug effects / Q000378:metabolism; D019108:Tight Junctions / Q000187:drug effects* / Q000378:metabolism; D062826:Zonula Occludens-1 Protein
C515334:CCR2 protein, human; D018932:Chemokine CCL2; D018765:Dopamine Uptake Inhibitors; D008565:Membrane Proteins; D010750:Phosphoproteins; D054390:Receptors, CCR2; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D003042:Cocaine