Anti-Inflammatory Effects of Omega-3 Fatty Acids in the Brain: Physiological Mechanisms and Relevance to Pharmacology

Abstract

Classically, polyunsaturated fatty acids (PUFA) were largely thought to be relatively inert structural components of brain, largely important for the formation of cellular membranes. Over the past 10 years, a host of bioactive lipid mediators that are enzymatically derived from arachidonic acid, the main n-6 PUFA, and docosahexaenoic acid, the main n-3 PUFA in the brain, known to regulate peripheral immune function, have been detected in the brain and shown to regulate microglia activation. Recent advances have focused on how PUFA regulate the molecular signaling of microglia, especially in the context of neuroinflammation and behavior. Several active drugs regulate brain lipid signaling and provide proof of concept for targeting the brain. Because brain lipid metabolism relies on a complex integration of diet, peripheral metabolism, including the liver and blood, which supply the brain with PUFAs that can be altered by genetics, sex, and aging, there are many pathways that can be disrupted, leading to altered brain lipid homeostasis. Brain lipid signaling pathways are altered in neurologic disorders and may be viable targets for the development of novel therapeutics. In this study, we discuss in particular how n-3 PUFAs and their metabolites regulate microglia phenotype and function to exert their anti-inflammatory and proresolving activities in the brain.

How to reprogram microglia toward beneficial functions

“…Independent of the inflammatory challenge applied (e.g., hypoxia, interferon-y, amyloid-β), cultured microglia consistently show decreased production of pro-inflammatory factors (De Smedt-Peyrusse et al, 2008), decreased COX2 and iNOS activity (Pettit, Varsanyi, Tadros, & Vassiliou, 2013;Zendedel et al, 2015) while exibit typical features of anti-inflammatory microglia, like CD206 surface expression and autophagy when treated with n-3 PUFAs (Chhor et al, 2013;Inoue et al, 2017). Many in vivo studies confirm that N-3 PUFA supplementation reduces detrimental microglia function (summarized in (Laye et al, 2018). Although microglia express a wide range of lipidsensitive receptors and lipid metabolism-related genes (Mauerer, Walczak, & Langmann, 2009;Mecha et al, 2015), the molecular link between bioactive fatty acids and their effects in microglia has not been completely clarified yet.…”

“…In fact, NADPH generated via glucose metabolism through the penthose phosphate pathway (PPP) is requisite cofactor for the pro- While SFA mainly act as pro-inflammatory stimuli (Z. Wang et al, 2012;Gao et al, 2014), N-3 PUFAs and their metabolites have emerged as anti-inflammatory modulators of microglial functions (Laye, Nadjar, Joffre, & Bazinet, 2018). Independent of the inflammatory challenge applied (e.g., hypoxia, interferon-y, amyloid-β), cultured microglia consistently show decreased production of pro-inflammatory factors (De Smedt-Peyrusse et al, 2008), decreased COX2 and iNOS activity (Pettit, Varsanyi, Tadros, & Vassiliou, 2013;Zendedel et al, 2015) while exibit typical features of anti-inflammatory microglia, like CD206 surface expression and autophagy when treated with n-3 PUFAs (Chhor et al, 2013;Inoue et al, 2017).…”

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

“…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] .…”

“…These mediators include oxylipins derived from cyclooxygenases (COX), lipoxygenases (LOX) and cytochrome P450 (CYP) pathways 1 that are involved in the regulation of inflammation and phagocytic activity of immune cells [5][6][7][8][9][10][11] . An overall increase in the dietary LA/ALA ratio and a reduction in LC n-3 PUFA intake, as found in the Western diet, leads to reduced DHA and increased AA levels in the brain 4,12 .…”

Immunological Dysfunction in Autism Spectrum Disorder: A Potential Target for Therapy

“…Omega-3 Omega-3 fatty acids have anti-inflammatory and immunomodulatory properties [151][152][153]. Supplementation with omega-3 decreases NF-κB, IL-12, and IL-13 gene expression [154], and levels of macrophage inflammatory protein (MIP)-2, IL-6 [155], IL-17A [156], and TNF-α [155][156][157][158].…”