General statements

Dr. Luisa Klotz
Department of Neurology, University of Bonn
Sigmund-Freud-Str. 25, 53105 Bonn
Tel.: +49-(0)228-287-11006
Fax: +49-(0)228-287-15024
e-mail: luisa.klotz@ukb.uni-bonn.de

Prof. Dr. Thomas Klockgether
Department of Neurology, University of Bonn
Sigmund-Freud-Str. 25, 53105 Bonn
Tel.: +49-(0)228-287-15736
Fax: +49-(0)228-287-15024
e-mail: klockgether@uni-bonn.de


Peroxisome-proliferator-activated receptor γ (PPARγ) in microglia during local inflammatory responses in experimental autoimmune encephalomyelitis (EAE)

Short title

Microglial PPARγ in central nervous system inflammation


PPARγ belongs to a receptor family of ligand-activated transcription factors involved in the regulation of inflammation. Besides its expression in cells of the peripheral immune compartment, it is also expressed in the central nervous system, especially in microglia and in neurons. While the peripheral activation of autoreactive encephalitogenic T cells is thought to be the first crucial step in the pathogenesis of MS and EAE, there is increasing evidence that local inflammatory responses within the central nervous system strongly contribute to the maintenance of disease pathology finally leading to demyelination as well as axonal and neuronal damage. Recently, the crucial role of activated microglial cells in this process has been clearly demonstrated; however, knowledge about the control of microglial function is still sparse. We therefore want to assess the role of PPARγ for microglial effector functions in vitro and in vivo.

In a first step, cultured primary microglial cells will be genetically modified either by cre-recombinase mediated ablation of endogenous PPARγ expression or by overexpression of PPARγ using lentiviral vectors. Phenotype and function of PPARγ-modulated microglia, i.e. phagocytosis, migration and T cell activation, will be studied under normal and inflammatory conditions and after additional activation of PPARγ using receptor agonists. Furthermore, possible neuroprotective effects of microglial PPARγ will be analyzed using cocultures of primary microglia and neurons. To assess the role of microglial PPARγ in vivo, we will employ a cre-lox approach to generate mice lacking PPARγ exclusively in the microglial compartment. In these mice, we aim to investigate whether loss of PPARγ results in microglial hyperreactivity under inflammatory conditions, which in turn may lead to an increase in demyelination and enhanced neurotoxicity during the effector phase of EAE.

The project aims to determine the protective role of PPARγ in brain microglial cells as a possible future target for specific therapeutic interventions in inflammatory CNS diseases, especially MS.