Dietary n-3 long chain PUFA supplementation promotes a pro-resolving oxylipin profile in the brain

Abstract

The brain is highly enriched in long chain polyunsaturated fatty acids (LC-PUFAs) that display immunomodulatory properties in the brain. At the periphery, the modulation of inflammation by LC-PUFAs occurs through lipid mediators called oxylipins which have anti-inflammatory and pro-resolving activities when derived from n-3 LC-PUFAs and pro-inflammatory activities when derived from n-6 LC-PUFAs. However, whether a diet rich in LC-PUFAs modulates oxylipins and neuroinflammation in the brain has been poorly investigated. In this study, the effect of a dietary n-3 LC-PUFA supplementation on oxylipin profile and neuroinflammation in the brain was analyzed. Mice were given diets deficient or supplemented in n-3 LC-PUFAs for a 2-month period starting at post-natal day 21, followed by a peripheral administration of lipopolysaccharide (LPS) at adulthood. We first showed that dietary n-3 LC-PUFA supplementation induced n-3 LC-PUFA enrichment in the hippocampus and subsequently an increase in n-3 PUFA-derived oxylipins and a decrease in n-6 PUFA-derived oxylipins. In response to LPS, n-3 LC-PUFA deficient mice presented a pro-inflammatory oxylipin profile whereas n-3 LC-PUFA supplemented mice displayed an anti-inflammatory oxylipin profile in the hippocampus. Accordingly, the expression of cyclooxygenase-2 and 5-lipoxygenase, the enzymes implicated in pro- and anti-inflammatory oxylipin synthesis, was induced by LPS in both diets. In addition, LPS-induced pro-inflammatory cytokine increase was reduced by dietary n-3 LC-PUFA supplementation. These results indicate that brain n-3 LC-PUFAs increase by dietary means and promote the synthesis of anti-inflammatory derived bioactive oxylipins. As neuroinflammation plays a key role in all brain injuries and many neurodegenerative disorders, the present data suggest that dietary habits may be an important regulator of brain cytokine production in these contexts.

Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the developing brain

“…Oxylipins are involved in the regulation of inflammation and phagocytic activity of immune cells 1,[9][10][11]54,[95][96][97] . Their production is largely influenced by n-3 PUFA dietary supply, including in the brain 54 . Using lipidomics, we examined their role in microglial phagocytic activity during development.…”

“…Microglia isolated from n-3 deficient mice had higher levels of free, unesterified, AA and lower quantities of free EPA, as determined by highperformance liquid chromatography with tandem mass spectrometry (LC-MS-MS) ( Figure 6A). When unesterified from the cellular membrane, free PUFAs are rapidly converted to bioactive mediators (or oxylipins) with potential effects on microglial cells 1,7,8,[51][52][53][54] .…”

The Brain Oxylipin Profile Is Resistant to Modulation by Dietary n‐6 and n‐3 Polyunsaturated Fatty Acids in Male and Female Rats

“…For example, n‐3 PUFA (EPA and DHA) supplementation increases some EPA‐derived and DHA‐derived oxylipins and decreases some ARA oxylipins in parts of or in whole brain compared to controls in animal models (Hashimoto et al, ; Ostermann et al, ). An n‐3 PUFA‐rich diet also reduced epoxy‐PUFA and the ratio of epoxy‐ to dihydroxy‐PUFA, an indication of higher soluble epoxide hydrolase activity (Ostermann et al, ), and promoted synthesis of proresolving oxylipins in the murine brain (Rey et al, ). Increased dietary n‐6 PUFA (LNA) feeding results in increased LNA and ARA oxylipins and decreased EPA oxylipins in the cerebral cortex of rat brain (Taha et al, ), while limiting dietary LNA reduces lipopolysaccharide (LPS)‐induced increases in the brain PGE 2 concentration (Taha et al, ).…”

Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells

“…In contrast to the deficiency, the supplementation in n-3 LC-PUFAs increases brain DHA [64][65][66][67]. DHA supplementation is more efficient than ALA supplementation to increase brain DHA [68,69]. A DHA supplementation is also efficient to reverse brain DHA decrease due to an n-3 PUFA deficiency or to aging [33, [70][71][72].…”

“…These Polyunsaturated Fatty Acid Metabolism in the Brain and Brain Cells DOI: http://dx.doi.org/10.5772/intechopen.88232 enzymes are expressed in the brain [90][91][92]. In response to lipopolysaccharide (LPS) that induces inflammation, COX-2 is rapidly expressed in the hippocampus [69,93] and inhibition of COX-2 delays resolution of acute inflammation [94]. 15-LOX and 5-LOX are the most abundant LOX in the brain [90].…”