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Anti-inflammatory and anti-apoptotic effects of LXR/RXR agonists in the central nervous system

Final Activity Report Summary - LXRNEUROINFLAMMATION (Anti-inflammatory and anti-apoptotic effects of LXR/RXR agonists in the central nervous system)

Neuroinflammation is a characteristic of pathological affected tissue in several neurodegenerative disorders, such as multiple sclerosis and intervention of the inflammatory process has gained attention as a therapeutic strategy to halt neurodegenerative disorders. One of the primary cell types in the central nervous system that contributes to neuroinflammation is microloglia, originally derived from monocytes/macrophages.

We have been studying the role of two transcription factors from the nuclear receptor superfamily, LXRalpha and beta, in microglial activation in response to cytokines produced at the inflammatory site. Recent findings support a protective role for LXRs in experimentally-induced diseases with a neuroinflammatory origin, such as murine experimental autoimmune encephalomyelitis, although the mechanisms that allow neuroprotection are not completely understood. Using gene profiling studies we have determined a subset of cytokine-regulated genes that are susceptible to down regulation by agonists for LXR.

In parallel, we have also determined a number of parameters of microglial function, such as proliferation, the production and release of pro-inflammatory mediators and their ability to phagocytose apoptotic bodies that are affected by LXR activation. Several lines of research have been initiated in order to understand the mechanism/s by which LXRs interfere with the different pathways of microglia activation, including signal transduction pathways and factors that directly transcriptional machinery. Furthermore, we have also analysed direct and indirect effects of LXR activation on survival of neuronal cells under different conditions of stress. The results of these studies are currently being organised for publication.