PhD of Charlotte Rey

Thesis supervisor: Corinne Joffre

Laboratory of Sophie Layé: NutriNeuro

Team of Lucile Capuron and Sophie Layé : Nutrition and Psychoneuroimmunology

Jury's members:

President: Pierre Gressens (DR INSERM, Paris)

Rapporteurs: Richard Bazinet (Toronto) and Niyazi Acar (CR INRA CSGA, Dijon)

Examinator: Pierre Gressens (DR INSERM Paris)

Invited: Carole Vaysse (ITERG, Pessac) and Sophie Layé (DR INRA NutriNeuro, Bordeaux)

Thesis supervisor: Corinne Joffre

RESUME

The brain is highly enriched in docosahexaenoic acid (DHA, n-3 polyunsaturated fatty acid, PUFA) and in arachidonic acid (n-6 PUFA) that are strong immunomodulators. They could be involved in the regulation of neuroinflammation through their conversion in bioactive lipid derivatives. Then, our objective was to define the role of n-3 PUFA derived lipid mediators that have anti-inflammatory and pro resolutive properties in the regulation of brain inflammation.

First, we characterized the impact of dietary n-3 PUFA modulation on brain lipid composition. In a central inflammatory model, n-3 PUFA intake induced 1) an increase in n-3 PUFA derived lipid metabolites, 2) a decrease in n-6 PUFA derived lipid mediators, and 3) a decrease in inflammation in the hippocampus. Moreover, n-3 PUFA intake during the perinatal period did not affect lipid composition of brain immune microglial cells. Then, we chose a therapeutic approach to demonstrate in vitro in microglial cells that RvD1 derived from DHA, through the binding on its receptor ALX-Fpr2, attenuated inflammation via the regulation of NFκB pathway and microRNA expressions. In vivo, intracerebral injection of RvD1 and DHA reduced inflammation in the hippocampus by different pathways.

Thus, the bioactive lipid derivatives from n-3 PUFA could be the mediators by which n-3 PUFA exert their beneficial effects on neuroinflammation, RvD1 playing a crucial role in this regulation.