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Activation of Peroxisome Proliferator-Activated Receptor (PPAR) Suppresses Rho GTPases in Human Brain Microvascular Endothelial Cells and Inhibits Adhesion and Transendothelial Migration of HIV-1 Infected Monocytes¹

Servio H. Ramirez^*,, David Heilman^*,, Brenda Morsey^*,, Raghava Potula^*,, James Haorah^*, and Yuri Persidsky^2,*,,

^* Center for Neurovirology and Neurodegenerative Disorders, Department of Pharmacology/Experimental Neuroscience, and Department of Pathology/Microbiology, University of Nebraska Medical Center, Omaha, NE 68198

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 PPAR activation. In contrast to non-brain-derived endothelial cells, PPAR 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 PPAR 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 PPAR agonist. These findings indicate that Rac1 and RhoA inhibition by PPAR agonists could be a new approach for treatment of neuroinflammation by preventing monocyte migration across the BBB.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants AA015913 and MH65151 from the National Institutes of Health (to Y.P.).

² Address correspondence and reprint requests to Dr. Yuri Persidsky, Departments of Pathology/Microbiology and Pharmacology/Experimental Neuroscience, 985215 Nebraska Medical Center, Omaha, NE 68198. E-mail address: ypersids{at}unmc.edu

³ Abbreviations used in this paper: BBB, blood brain barrier; BMVEC, human brain microvascular endothelial cells; PPAR, peroxisome proliferator-activated receptors; TEER, transendothelial electrical resistance; TZD, thiazolidinediones; shRNA, small hairpin RNA; TJ, tight junction; WT, wild type; CA, constitutively active; DN, dominant negative.

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