Brain endothelial PPAR-gamma controls inflammation-induced CD4+ T cell adhesion and transmigration in vitro

An important step in the pathogenesis of multiple sclerosis is the adhesion and subsequent transmigration of activated encephalitogenic CD4+ T cells across highly specialized endothelial cells (EC) participating in the formation of the blood-brain-barrier. Recruitment of CD4+ T cells across brain EC relies on interaction with EC-expressed adhesion molecules that allow immune surveillance of the CNS, but also promote CNS invasion by encephalitogenic T cells under inflammatory conditions.

Our results provide molecular evidence that the transcription factor peroxisome proliferator-activated receptor gamma (PPARg) is a negative regulator of brain EC inflammation. PPARg activation in brain ECs by the PPARg agonist pioglitazone significantly reduces transendothelial migration of encephalitogenic T cells across TNFa-stimulated brain EC. This effect is clearly PPARg mediated, as lentiviral PPARg overexpression in EC results in selective abrogation of inflammation-induced T cell adhesion and subsequent transmigration, but permits adhesion and transmigration of T cells under non-inflammatory conditions.

Moreover, PPARg overexpression in EC prevented TNFa-induced upregulation of the adhesion molecules ICAM-1 and VCAM-1. We therefore propose that PPARg activation in EC selectively curtails inflammation-induced EC-T cell interactions and may therefore be exploited to selectively target detrimental EC-T cell interactions under inflammatory conditions.