International Journal of Molecular Sciences Review Effects of Omega-3 Fatty Acids on Immune Cells Saray Gutiérrez, Sara L Svahn and Maria E Johansson * Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden; [email protected] (S.G.); [email protected] (S.L.S.) * Correspondence: [email protected]; Tel.: +46-31-786-3556; Fax: +46-31-786-3512 Received: 6 September 2019; Accepted: 2 October 2019; Published: 11 October 2019 Abstract: Alterations on the immune system caused by omega-3 fatty acids have been described for 30 years. This family of polyunsaturated fatty acids exerts major alterations on the activation of cells from both the innate and the adaptive immune system, although the mechanisms for such regulation are diverse. First, as a constitutive part of the cellular membrane, omega-3 fatty acids can regulate cellular membrane properties, such as membrane fluidity or complex assembly in lipid rafts. In recent years, however, a new role for omega-3 fatty acids and their derivatives as signaling molecules has emerged. In this review, we describe the latest findings describing the effects of omega-3 fatty acids on different cells from the immune system and their possible molecular mechanisms. Keywords: polyunsaturated fatty acids; PUFAs; omega-3 fatty acids; α-linolenic acid; ALA; eicosapentaenoic acid; EPA; docosahexaenoic acid; DHA; immune cells; immune response; phagocytosis; immune-modulation; anti-inflammatory; migration; presentation; cytokines; antibody production 1. Introduction The immune system is a defense system that protects organisms from invading pathogens, such as viruses or bacteria. It comprises a heterogeneous group of cells, i.e., immune cells, as well as cell-independent mechanisms. Immune cells can be broadly divided into two main categories according to their properties and defense mechanisms: cells of the innate and cells of the adaptive immune system. Cells from the innate immune system, namely macrophages, neutrophils, eosinophils, basophils, mast cells, natural killer cells, and dendritic cells, are the first cellular line of defense. Their mode of action is generally fast but with limited specificity. Cells from the adaptive immune system, namely B cells and T cells, have a higher level of specificity, but their activation is delayed. However, cells from the adaptive immune system develop memory against pathogens after a first confrontation, and their speed and efficiency against a previously faced pathogen is greatly enhanced during a second encounter. Coordination of the different immune cells and regulation of their activity is of crucial importance for mounting an effective immune defense. This task is often accomplished by the secretion of cytokines and chemokines, i.e., molecules secreted by cells, including but not restricted to immune cells, that attract immune cells into the site of infection and regulate their activation or their suppression [1,2]. A healthy and balanced diet is essential for the correct function of every part of our organism, including the immune system. Additionally, some dietary factors have been found to have immune-regulatory properties, including micronutrients such as Vitamin D or macronutrients such as fatty acids [3]. The impact of dietary polyunsaturated fatty acids (PUFAs) on the immune system has been investigated for decades, with special focus on the omega-3 PUFAs α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). ALA is found in nuts and seeds whereas EPA and DHA are the main components of fish oil [4,5]. For a comprehensive review of the sources of omega-3 fatty acids, we recommend Cholewski et al. [6]. Int. J. Mol. Sci. 2019, 20, 5028; doi:10.3390/ijms20205028 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, 5028 2 of 21 Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 2 of 21 EPAwhereas and EPA DHA and DHA can alsoare the be main synthesized components from of fish ALA oil [4,5]. [7], For a a process comprehensive that involves review of severalthe steps orchestratedsources of by omega-3 multiple fattyelongases, acids, we recommend desaturases, Cholewski and β et-oxidases al. [6]. [8]. However, the synthesis of EPA from ALAEPA occurs and DHA at a low can ratealso inbe mammalssynthesized [ 9from]. Of ALA note, [7], the a sameprocess enzymes that involves are employedseveral steps by omega-6 fattyorchestrated acids for their by multiple metabolic elongases, pathways. desaturases, and β-oxidases [8]. However, the synthesis of EPA Bothfrom ALA omega-3 occurs and at a low omega-6-derived rate in mammals metabolites[9]. Of note, the have same important enzymes are immune-regulatory employed by omega- functions. 6 fatty acids for their metabolic pathways. These metabolites are generally known as pro-resolving mediators (SPMs) and can be classified Both omega-3 and omega-6-derived metabolites have important immune-regulatory functions. in diffTheseerent metabolites families—prostaglandins, are generally known leukotrienes, as pro-resolving thromboxanes, mediators (SPMs) maresins, and can protectins, be classified and in resolvins. Theirdifferent synthesis families—prostaglandins, is orchestrated by cyclooxygenase, leukotrienes, thromboxanes, lipoxygenase, maresins, or protectins, cytochrome and P450resolvins. enzymes [10]. A summaryTheir synthesis of the is metabolites orchestrated producedby cyclooxygenase from omega-3, lipoxygenase, fatty or acids cytochrome and the P450 enzymes enzymes regulating [10]. their synthesisA summary is found of the in Figuremetabolites1. Omega-3 produced and from omega-6 omega-3 substrates fatty acids competeand the enzymes for these regulating enzymes their [ 11 ], as well as forsynthesis the above is found mentioned in Figure elongases 1. Omega-3 and and elastases. omega-6 substrates Therefore, compete in the for presence these enzymes of omega-3 [11], as fatty acids, well as for the above mentioned elongases and elastases. Therefore, in the presence of omega-3 fatty the competition for the enzymes reduces the synthesis of omega-6-derived metabolites, which also acids, the competition for the enzymes reduces the synthesis of omega-6-derived metabolites, which havealso effects have on effects immune on immune cells. This cells. competition This competition constitutes constitutes an additionalan additional level level of of immune-regulation immune- by omega-3regulation fatty by omeg acids.a-3 fatty acids. FigureFigure 1. Main 1. Main biochemical biochemical pathways pathways for for the the synthesissynthesis of of omega-3 omega-3 derived derived metabolites. metabolites. The The figure showsfigure the omega-3 shows the fatty omega-3 acids α fatty-linolenic acids acidα-linolenic (ALA), acid eicosapentaenoic (ALA), eicosapentaenoic acid (EPA), acid and (EPA), docosahexaenoic and docosahexaenoic acid (DHA), their downstream metabolites and the enzymes acid (DHA), their downstream metabolites and the enzymes regulating their synthesis. regulating their synthesis. 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Effects of Omega-3 Fatty Acids on Macrophage Function Macrophages have a fundamental role as part of the innate immune system. They patrol multiple organs in a constant search for invading pathogens. They are able to recognize specific Int. J. Mol. Sci. 2019, 20, 5028 3 of 21 pathogen-associated molecular patterns (PAMPs) thanks to the toll-like