Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) suppresses Rho GTPases in human brain microvascular endothelial cells and inhibits adhesion and transendothelial migration of HIV-1 infected monocytes.
Under inflammatory conditions (including HIV-1 encephalitis and multiple sclerosis), activated brain endothelium enhances the adhesion and transmigration of monocytes across the blood-brain barrier (BBB). Synthetic ligands that activate the peroxisome proliferator-activated receptors (PPARs) have anti-inflammatory properties, and PPAR stimulation prevents the interaction of leukocytes with cytokine stimulated-endothelium. However, the mechanism underlying these effects of PPAR ligands and their ability to intervene with leukocyte adhesion and migration across brain endothelial cells has yet to be explored. For the first time, using primary human brain endothelial cells (BMVEC), we demonstrated that monocyte adhesion and transendothelial migration across inflamed endothelium were markedly reduced by PPARgamma activation. In contrast to non-brain-derived endothelial cells, PPARalpha activation in the BMVEC had no significant effect on monocyte-endothelial interaction. Previously, our work indicated a critical role of Rho GTPases (like RhoA) in BMVEC to control migration of HIV-1 infected monocytes across BBB. In this study, we show that in the BMVEC PPARgamma stimulation prevented activation of two GTPases, Rac1 and RhoA, which correlated with decreased monocyte adhesion to and migration across brain endothelium. Relevant to HIV-1 neuropathogenesis, enhanced adhesion and migration of HIV-1 infected monocytes across the BBB were significantly reduced when BMVEC were treated with PPARgamma agonist. These findings indicate that Rac1 and RhoA inhibition by PPARgamma agonists could be a new approach for treatment of neuroinflammation by preventing monocyte migration across the BBB.
Ramirez
Servio H
SH
Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha 68198, USA.
Heilman
David
D
Morsey
Brenda
B
Potula
Raghava
R
Haorah
James
J
Persidsky
Yuri
Y
D001812:Blood-Brain Barrier / Q000276:immunology*; D001921:Brain / Q000098:blood supply; D002196:Capillaries / Q000201:enzymology / Q000276:immunology; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000201:enzymology / Q000276:immunology; D015497:HIV-1; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors
D047495:PPAR gamma; D034741:RNA, Small Interfering; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D018799:Intercellular Adhesion Molecule-1; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein