Activation of peroxisome proliferator-activated receptor γ (PPARγ) suppresses rho GTPases in human brain microvascular endothelial cells and inhibits adhesion and transendothelial migration of HIV-1 infected monocytes

Servio H. Ramirez, David Heilman, Brenda Morsey, Raghava Potula, James Haorah, Yuri Persidsky

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)1854-1865
Number of pages12
JournalJournal of Immunology
Volume180
Issue number3
DOIs
StatePublished - Feb 1 2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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