Abstract
Polyunsaturated fatty acids (PUFAs) display immunomodulatory properties in the brain, n-3 PUFAs being able to reduce inflammation whereas n-6 PUFAs are more pro-inflammatory. It has been extensively demonstrated that exposure to a peripheral immune challenge leads to the production and release of inflammatory mediators in the brain in association with cognitive deficits. The question arises whether n-3 PUFA supplementation could downregulate the brain inflammatory response and subsequent cognitive alterations. In this study, we used a genetically modified mouse line carrying the fat-1 gene from the roundworm Caenorhabditis elegans, encoding an n-3 PUFA desaturase that catalyzes conversion of n-6 into n-3 PUFA. Consequently, these mice display endogenously elevated n-3 PUFA tissue contents. Fat-1 mice or wild-type (WT) littermates were injected peripherally with lipopolysaccharide (LPS), a bacterial endotoxin, to induce an inflammatory episode. Our results showed that LPS altered differently the phenotype of microglia and the expression of cytokines and chemokines in Fat-1 and WT mice. In Fat-1 mice, pro-inflammatory factors synthesis was lowered compared with WT mice, whereas anti-inflammatory mechanisms were favored 24 h after LPS treatment. Moreover, LPS injection impaired spatial memory in WT mice, whereas interestingly, the Fat-1 mice showed normal cognitive performances. All together, these data suggest that the central n-3 PUFA increase observed in Fat-1 mice modulated the brain innate immune system activity, leading to the protection of animals against LPS-induced pro-inflammatory cytokine production and subsequent spatial memory alteration.
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Acknowledgements
We thank Dr Guillaume Ferreira for helpful comments on the manuscript. We also thank Dr Guillaume Ferreira and Pr Muriel Darnaudery for helping with behavioral experiments. We acknowledge the technical support from V. Pitard and S. Gonzalez from the cytometry platform at the Structure Federative de Recherche TransBioMed at the University of Bordeaux Segalen. We thank J.C. Helbling and C. Tridon for transgenic mice genotyping. We also thank P. Birac, C. Tridon, and M. Cadet for taking care of the mice. This research was financially supported by INRA, ANR, and Fondation pour la Recherche Medicale (FRM). JCD is the recipient of a postdoctoral fellowship from the Région Aquitaine. This project was also supported by the grant LABEX BRAIN ANR-10-LABX-43.
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Delpech, JC., Madore, C., Joffre, C. et al. Transgenic Increase in n-3/n-6 Fatty Acid Ratio Protects Against Cognitive Deficits Induced by an Immune Challenge through Decrease of Neuroinflammation. Neuropsychopharmacol 40, 525–536 (2015). https://doi.org/10.1038/npp.2014.196
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DOI: https://doi.org/10.1038/npp.2014.196
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