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Obesity is associated with a wide range of complications, including type 2 diabetes mellitus, cardiovascular disease, hypertension and nonalcoholic fatty liver disease. Obesity also increases the incidence and progression of cancers, autoimmunity and infections, as well as lowering vaccine responsiveness. A unifying concept across these differing diseases is dysregulated immunity, particularly inflammation, in response to metabolic overload. Herein, we review emerging mechanisms by which obesity drives inflammation and autoimmunity, as well as impairing tumour immunosurveillance and the response to infections. Among these mechanisms are obesity-associated changes in the hormones that regulate immune cell metabolism and function and drive inflammation. The cargo of extracellular vesicles derived from adipose tissue, which controls cytokine secretion from immune cells, is also dysregulated in obesity, in addition to impairments in fatty acid metabolism related to inflammation. Furthermore, an imbalance exists in obesity in the biosynthesis and levels of polyunsaturated fatty acid-derived oxylipins, which control a range of outcomes related to inflammation, such as immune cell chemotaxis and cytokine production. Finally, there is a need to investigate how obesity influences immunity using innovative model systems that account for the heterogeneous nature of obesity in the human population. In this Review, the emerging cellular and molecular mechanisms by which obesity impairs key aspects of immunity are discussed, including changes in the abundance of key hormones, dysregulation of adipose-tissue-derived extracellular vesicles and dysregulation of polyunsaturated fatty acid metabolism. Key points: Obesity dysregulates immunity through differing mechanisms, which contribute to a range of secondary complications. Obesity influences the level and function of nutritionally regulated hormones that regulate signalling pathways that mediate immune cell metabolism and function and drive inflammation. Expansion of adipose tissue dysregulates the abundance and composition of extracellular vesicles, which carry a wide range of cargo that can affect the activity of immune cells and lipid metabolism. Increased adiposity dysregulates polyunsaturated fatty acid metabolism; notably, the concentration of oxylipins synthesized from polyunsaturated fatty acids, which control a range of outcomes related to inflammation, is imbalanced in obesity. Investigating immunity in obesity requires translation from inbred rodents to humans; one approach is to use Diverse Outbred and Collaborative Cross mouse populations that can model the heterogeneous nature of human obesity. [ABSTRACT FROM AUTHOR]

Inhaled toxicants drive the onset of and exacerbate preexisting chronic pulmonary diseases, however, the biological mechanisms by which this occurs are largely unknown. Exposure to inhaled toxicants, both environmental and occupational, drives pulmonary inflammation and injury. Upon activation of the inflammatory response, polyunsaturated fatty acids (PUFAs) are metabolized into predominately proinflammatory lipid mediators termed eicosanoids which recruit immune cells to the site of injury, perpetuating inflammation to clear the exposed toxicants. Following inflammation, lipid mediator class-switching occurs, a process that leads to increased metabolism of hydroxylated derivates of PUFAs. These mediators, which include mono-hydroxylated PUFA derivatives and specialized proresolving lipid mediators, initiate an active process of inflammation resolution by inhibiting the inflammatory response and activating resolution pathways to return the tissue to homeostasis. Exposure to inhaled toxicants leads to alterations in the synthesis of these proinflammatory and proresolving lipid mediator pathways, resulting in greater pulmonary inflammation and injury, and increasing the risk for the onset of chronic lung diseases. Recent studies have begun utilizing supplementation of PUFAs and their metabolites as potential therapeutics for toxicant-induced pulmonary inflammation and injury. Here we will review the current understanding of the lipid mediators in pulmonary inflammation and resolution as well as the impact of dietary fatty acid supplementation on lipid mediator-driven inflammation following air pollution exposure. [ABSTRACT FROM AUTHOR]

Background: Metabolic pathways are related to physiological functions and disease states and are influenced by genetic variation and environmental factors. Hispanics/Latino individuals have ancestry-derived genomic regions (local ancestry) from their recent admixture that have been less characterized for associations with metabolite abundance and disease risk. Methods: We performed admixture mapping of 640 circulating metabolites in 3887 Hispanic/Latino individuals from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Metabolites were quantified in fasting serum through non-targeted mass spectrometry (MS) analysis using ultra-performance liquid chromatography-MS/MS. Replication was performed in 1856 nonoverlapping HCHS/SOL participants with metabolomic data. Results: By leveraging local ancestry, this study identified significant ancestry-enriched associations for 78 circulating metabolites at 484 independent regions, including 116 novel metabolite-genomic region associations that replicated in an independent sample. Among the main findings, we identified Native American enriched genomic regions at chromosomes 11 and 15, mapping to FADS1/FADS2 and LIPC, respectively, associated with reduced long-chain polyunsaturated fatty acid metabolites implicated in metabolic and inflammatory pathways. An African-derived genomic region at chromosome 2 was associated with N-acetylated amino acid metabolites. This region, mapped to ALMS1, is associated with chronic kidney disease, a disease that disproportionately burdens individuals of African descent. Conclusions: Our findings provide important insights into differences in metabolite quantities related to ancestry in admixed populations including metabolites related to regulation of lipid polyunsaturated fatty acids and N-acetylated amino acids, which may have implications for common diseases in populations. [ABSTRACT FROM AUTHOR]

Obesity is a major independent risk factor for increased morbidity and mortality upon infection with Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), which is responsible for the current coronavirus disease pandemic (COVID-19). Therefore, there is a critical need to identify underlying metabolic factors associated with obesity that could be contributing toward increased susceptibility to SARS-CoV-2 in this vulnerable population. Here, we focus on the critical role of potent endogenous lipid metabolites known as specialized pro-resolving mediators (SPMs) that are synthesized from polyunsaturated fatty acids. SPMs are generated during the transition of inflammation to resolution and have a vital role in directing damaged tissues to homeostasis; furthermore, SPMs display anti-viral activity in the context of influenza infection without being immunosuppressive. We cover evidence from rodent and human studies to show that obesity, and its co-morbidities, induce a signature of SPM deficiency across immunometabolic tissues. We further discuss how the effects of obesity upon SARS-CoV-2 infection are likely exacerbated with environmental exposures that promote chronic pulmonary inflammation and augment SPM deficits. Finally, we highlight potential approaches to overcome the loss of SPMs using dietary and pharmacological interventions. Collectively, this mini-review underscores the need for mechanistic studies on how SPM deficiencies driven by obesity and environmental exposures may exacerbate the response to SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Obesity dysregulates B cell populations, which contributes toward poor immunological outcomes. We previously reported that differing B cell subsets are lowered in the bone marrow of obese male mice. Here, we focused on how lipid metabolites synthesized from docosahexaenoic acid (DHA) known as specialized pro‐resolving lipid mediators (SPMs) influence specific B cell populations in obese male mice. Metabololipidomics revealed that splenic SPM precursors 14‐hydroxydocosahexaenoic acid (14‐HDHA), 17‐hydroxydocosahexaenoic acid (17‐HDHA), and downstream protectin DX (PDX) were decreased in obese male C57BL/6J mice. Simultaneous administration of these mediators to obese mice rescued major decrements in bone marrow B cells, modest impairments in the spleen, and circulating IgG2c, which is pro‐inflammatory in obesity. In vitro studies with B cells, flow cytometry experiments with ALOX5−/− mice, and lipidomic analyses revealed the lowering of 14‐HDHA/17‐HDHA/PDX and dysregulation of B cell populations in obesity was driven indirectly via B cell extrinsic mechanisms. Notably, the lowering of lipid mediators was associated with an increase in the abundance of n‐6 polyunsaturated fatty acids, which have a high affinity for SPM‐generating enzymes. Subsequent experiments revealed female obese mice generally maintained the levels of SPM precursors, B cell subsets, and antibody levels. Finally, obese human females had increased circulating plasma cells accompanied by ex vivo B cell TNFα and IL‐10 secretion. Collectively, the data demonstrate that DHA‐derived mediators of the SPM pathway control the number of B cell subsets and pro‐inflammatory antibody levels in obese male but not female mice through a defect that is extrinsic to B cells. [ABSTRACT FROM AUTHOR]

Marine long chain n-3 polyunsaturated fatty acids (PUFA), eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), are bioactive molecules with clinical applications for the treatment of several diseases. In order to effectively translate these molecules into clinical trials, it is essential to establish the underlying mechanisms for n-3 PUFA. This review focuses on efforts to understand how EPA and DHA, upon incorporation into plasma membrane phospholipids, remodel the molecular organization of cholesterol-enriched lipid microdomains. We first give an overview of results from studies on cells. Paradoxical data generated from mouse studies indicate that EPA and DHA incorporate into lipid microdomains, yet in spite of their high disorder increase molecular order within the domain. We then spotlight the utility of solid state 2 H NMR spectroscopy of model bilayers as a tool for elucidating underlying mechanisms by which n-3 PUFA-containing phospholipids can regulate molecular organization of lipid microdomains. Evidence is presented demonstrating that n-3 PUFA exert differential structural effects when incorporated into phosphatidylethanolamines (PE) compared to phosphatidylcholines (PC), which explains some of the conflicting results observed in vivo. Recent studies that reveal differences between the interactions of EPA and DHA with lipid microdomains, potentially reflecting a differential in bioactivity, are finally described. Overall, we highlight the notion that NMR experiments on model membranes suggest a complex model by which n-3 PUFA reorganize lipid microdomains in vivo. This article is part of a Special Issue entitled: NMR Spectroscopy for Atomistic Views of Biomembranes and Cell Surfaces. Guest Editors: Lynette Cegelski and David P. Weliky. [ABSTRACT FROM AUTHOR]

Docosahexaenoic acid ( DHA) and eicosapentaenoic acid ( EPA) are bioactive n-3 long-chain polyunsaturated fatty acids ( LCPUFAs) in fish oil that exert immunosuppressive effects. A significant amount of literature shows that n-3 LCPUFAs suppress dendritic cell ( DC) function in vitro; however, few studies have determined if the effects are emulated at the animal level. In this study, we first focused on the functional consequences of 5% (weight/weight) fish oil on splenic CD11c+ DCs. Administration of n-3 LCPUFAs, modelling human pharmacological intake (2% of total kcal from EPA,1·3% from DHA), to C57 BL/6 mice for 3 weeks reduced DC surface expression of CD80 by 14% and tumour necrosis factor-α secretion by 29% upon lipopolysaccharide stimulation relative to a control diet. The n-3 LCPUFAs also significantly decreased CD11c+ surface expression and phagocytosis by 12% compared with the control diet. Antigen presentation studies revealed a 22% decrease in CD69 surface expression on transgenic CD4+ T lymphocytes activated by DCs from mice fed fish oil. We then determined if the functional changes were mechanistically associated with changes in lipid microdomain clustering or plasma membrane microviscosity with n-3 LCPUFAs, as reported for B and T lymphocytes. Fish oil administration to mice did not influence cholera-toxin induced lipid microdomain clustering or microviscosity, even though EPA and DHA levels were significantly elevated relative to the control diet. Overall, our data show that n-3 LCPUFAs exert immunosuppressive effects on DCs, validating in vitro studies. The results also show that DC microdomain clustering and microviscosity were not changed by the n-3 LCPUFA intervention used in this study. [ABSTRACT FROM AUTHOR]

Abstract: N-3 polyunsaturated fatty acids (PUFAs) from fish oil exert their functional effects by targeting multiple mechanisms. One mechanism to emerge in the past decade is the ability of n-3 PUFA acyl chains to perturb the molecular organization of plasma membrane sphingolipid/cholesterol-enriched lipid raft domains. These domains are nanometer-scale assemblies that coalesce to compartmentalize select proteins for optimal function. Here we review recent evidence on how n-3 PUFAs modify lipid rafts from biophysical and biochemical experiments from several different model systems. A central theme emerges from these studies. N-3 PUFA acyl chains display tremendous conformational flexibility and a low affinity for cholesterol and saturated acyl chains. This unique flexibility of n-3 PUFA acyl chains impacts the organization of inner and outer leaflet lipid rafts by disrupting acyl chain packing and molecular order within rafts. Ultimately, the disruption in raft organization has consequences for protein clustering and thereby signaling. Overall, elucidating the complex mechanisms by which n-3 PUFA acyl chains reorganize membrane architecture will enhance the translation of these fatty acids into the clinic for treating several diseases. [Copyright &y& Elsevier]

Abstract: Polyunsaturated fatty acids (PUFAs), notably of the n-3 series, have immunosuppressive effects which make these molecules candidates for treating inflammatory symptoms associated with cardiovascular disease, obesity, arthritis, and asthma. However, immunosuppression by PUFAs could increase susceptibility to bacterial and viral infection. A detailed molecular picture is required in order to understand the balance between the benefits and risks of utilizing PUFAs as adjuvant immunosuppressants. Here we review evidence that incorporation of PUFAs into membrane lipids of antigen presenting cells (APCs) downregulates APC function. We propose that PUFAs modulate antigen presentation by altering the organization of lipid and protein molecules of the plasma membrane and endomembranes; this alters recognition and responses by T cells. The foundation of our hypothesis is built on data from artificial bilayer experiments which provide the physical principles by which PUFA acyl chains affect membrane architecture. This review also reconciles conflicting results in the literature by discussing the advantages and disadvantages of differing methods of PUFA treatment of cells. We suggest that membrane modulation of immune cells may be an important and overlooked mechanism of immunomodulation. In addition, we propose that mechanistic studies with defined experimental protocols will speed the translation of laboratory studies on PUFAs to the clinic. [Copyright &y& Elsevier]

The major mammalian plasma membrane lipids are phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), and cholesterol. Whereas PC-cholesterol interactions are well studied, far less is known about those between PE and cholesterol. Here, we investigated the molecular organization of cholesterol in PEs that vary in their degree of acyl chain unsaturation. For heteroacid sn-1 saturated (palmitoyl), sn-2 unsaturated (various acyl chain) PEs, cholesterol solubility determined by X-ray diffraction was essentially identical with 1 (oleoyl, 51 ± 3 mol %) and 2 (linoleoyl, 49 ± 2 mol %) double bonds before decreasing progressively with 4 (arachidonyl, 41 + 3 mol %) and 6 (docosahexaenoyl, 31 + 3 mol %) double bonds. With 6 double bonds in each chain, cholesterol solubility was further reduced to 8.5 ± 1 mol %. However, ²H NMR experiments established that the orientation of cholesterol in the same heteroacid PE membranes was unaffected by the degree of acyl chain unsaturation. A tilt angle of 15 ± 1° was measured when equimolar [3α-²H1]cholesterol was added, regardless of the number of double bonds in the sn-2 chain. The finding that solubility of cholesterol in sn-1 saturated PEs depends on the amount of polyunsaturation in the sn-2 chain of PE differs from the equivalent PCs that universally incorporate ~50 mol % sterol. Unlike PCs, a differential in affinity for cholesterol and tendency to drive lateral segregation is inferred between polyunsaturated PEs. This distinction may have biological implications reflected by the health benefits of dietary polyunsaturated fatty acids that are often taken up into PE > PC. [ABSTRACT FROM AUTHOR]

Polyunsaturated fatty acids, PUFAs, can be used as adjuvant immunosuppressants for alleviating symptoms associated with inflammatory disorders. However, it is unclear if PUFA's immunosuppressive effects also alter susceptibility to infection. Here we show that PUFAs downregulate T cell immune responses in vitro by modulating MHC class I antigen presentation. Incorporation of the ω-6 PUFA arachidonic acid (AA) or the ω-3 PUFA docosahexaenoic acid (DHA) into membrane lipids of antigen-presenting cells, APCs, alters membrane microviscosity, increases lipid droplet formation and significantly reduces susceptibility of the cells to lysis by CD8+ T cells. PUFA modification lowers MHC class I surface expression by lowering the rate of forward trafficking of newly synthesized molecules from the ER to Golgi; however, calibration experiments show this reduction in surface MHC I expression is not sufficient to account for reduced lysis. PUFA treatment also lowers APC-T cell conjugate formation suggesting that AA and DHA could lower lysis by interfering with the formation of the immunological synapse as a consequence of changes in the lipid profile of APCs. Our data suggest that elimination of pathogen-derived peptides could be compromised by using PUFAs as immunosuppressants. In addition, PUFA mediated changes in trafficking of MHC class I molecules point to a new area of lipid modulation of immune responses. [ABSTRACT FROM AUTHOR]

B cell antigen presentation, cytokine production, and antibody production are targets of pharmacological intervention in inflammatory and infectious diseases. Here we review recent pre-clinical evidence demonstrating that pharmacologically relevant levels of n-3 polyunsaturated fatty acids (PUFA) derived from marine fish oils influence key aspects of B cell function through multiple mechanisms. N-3 PUFAs modestly diminish B cell mediated stimulation of classically defined naïve CD4 + Th1 cells through the major histocompatibility complex (MHC) class II pathway. This is consistent with existing data showing that n-3 PUFAs suppress the activation of Th1/Th17 cells through direct effects on helper T cells and indirect effects on antigen presenting cells. Mechanistically, n-3 PUFAs lower antigen presentation and T cell signaling by disrupting the formation of lipid microdomains within the immunological synapse. We then review data to show that n-3 PUFAs boost B cell activation and antibody production in the absence and presence of antigen stimulation. This has potential benefits for several clinical populations such as the aged and obese that have poor humoral immunity. The mode of action by which n-3 PUFA boost B cell activation and antibody production remains unclear, but may involve Th2 cytokines, enhanced production of specialized proresolving lipid mediators, and targeting of protein lateral organization in lipid microdomains. Finally, we highlight evidence to show that different n-3 PUFAs are not biologically equivalent, which has implications for the development of future interventions to target B cell activity. [ABSTRACT FROM AUTHOR]

Chronic inflammation contributes toward the pathogenesis of numerous diseases including, but not limited to, obesity, autoimmunity, cardiovascular diseases, and cancers. The discovery of specialized pro-resolving mediators (SPMs), which are critical for resolving inflammation, has commenced investigation into targeting pathways of inflammation resolution to improve physiological outcomes. SPMs are predominately synthesized from the n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. Therefore, one viable strategy to promote inflammation resolution would be to increase dietary intake of EPA/DHA, which are deficient in select populations. However, there are inconsistencies between the use of EPA/DHA as dietary or pharmacological supplements and improved inflammatory status. Herein, we review the literature on the relationship between the high n-6/n-3 PUFA ratio, downstream SPM biosynthesis, and inflammatory endpoints. We highlight key studies that have investigated how dietary intake of EPA/DHA increase tissue SPMs and their effects on inflammation. We also discuss the biochemical pathways by which EPA/DHA drive SPM biosynthesis and underscore mechanistic gaps in knowledge about these pathways which include a neglect for host genetics/ethnic differences in SPM metabolism, sexual dimorphism in SPM levels, and potential competition from select dietary n-6 PUFAs for enzymes of SPM synthesis. Altogether, establishing how dietary PUFAs control SPM biosynthesis in a genetic- and sex-dependent manner will drive new precision nutrition studies with EPA/DHA to prevent chronic inflammation in select populations. • The western diet is generally low in long chain n-3 PUFAs. • Low dietary n-3 PUFAs may contribute to a pro-inflammatory profile. • PUFA-derived SPM levels are unbalanced in chronic inflammatory diseases. • SNPs in enzymes of SPM biosynthesis may have direct clinical translation. • Establishing genetic differences in SPM metabolism will drive precision studies. [ABSTRACT FROM AUTHOR]

Eicosapentaenoic (EPA, 20:5), docosahexaenoic (DHA, 22:6) and docosapentaenoic (DPA, 22:5) acids are omega-3 polyunsaturated fatty acids (n-3 PUFA) obtained from dietary consumption of fish oils that potentially alleviate the symptoms of a range of chronic diseases. We focus here on the plasma membrane as a site of action and investigate how they affect molecular organization when taken up into a phospholipid. All atom MD simulations were performed to compare 1-stearoyl-2-eicosapentaenoylphosphatylcholine (EPA-PC, 18:0-20:5PC), 1-stearoyl-2-docosahexaenoylphosphatylcholine (DHA-PC, 18:0-22:6PC), 1-stearoyl-2-docosapentaenoylphosphatylcholine (DPA-PC, 18:0-22:5PC) and, as a monounsaturated control, 1-stearoyl-2-oleoylphosphatidylcholine (OA-PC, 18:0-18:1PC) bilayers. They were run in the absence and presence of 20 mol% cholesterol. Multiple double bonds confer high disorder on all three n-3 PUFA. The different number of double bonds and chain length for each n-3 PUFA moderates the reduction in membrane order exerted (compared to OA-PC, S ¯ CD = 0.152 ). EPA-PC ( S ¯ CD = 0.131 ) is most disordered, while DPA-PC ( S ¯ CD = 0.140 ) is least disordered. DHA-PC ( S ¯ CD = 0.139 ) is, within uncertainty, the same as DPA-PC. Following the addition of cholesterol, order in EPA-PC ( S ¯ CD = 0.169 ), DHA-PC ( S ¯ CD = 0.178 ) and DPA-PC ( S ¯ CD = 0.182 ) is increased less than in OA-PC ( S ¯ CD = 0.214 ). The high disorder of n-3 PUFA is responsible, preventing the n-3 PUFA-containing phospholipids from packing as close to the rigid sterol as the monounsaturated control. Our findings establish that EPA, DHA and DPA are not equivalent in their interactions within membranes, which possibly contributes to differences in clinical efficacy. [ABSTRACT FROM AUTHOR]

The long-chain n-3 polyunsaturated fatty acids (LC-PUFAs) eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) in fish oil have immunomodulatory properties. B cells are a poorly studied target of EPA/DHA in humans. Therefore, in this pilot study, we tested how n-3 LC-PUFAs influence B-cell responses of obese humans. Obese men and women were assigned to consume four 1-g capsules per day of olive oil (OO, n=12), fish oil (FO, n=12) concentrate or high-DHA-FO concentrate (n=10) for 12 weeks in a parallel design. Relative to baseline, FO (n=9) lowered the percentage of circulating memory and plasma B cells, whereas the other supplements had no effect. There were no postintervention differences between the three supplements. Next, ex vivo B-cell cytokines were assayed after stimulation of Toll-like receptors (TLRs) and/or the B-cell receptor (BCR) to determine if the effects of n-3 LC-PUFAs were pathway-dependent. B-cell IL-10 and TNFα secretion was respectively increased with high DHA-FO (n=10), relative to baseline, with respective TLR9 and TLR9+BCR stimulation. OO (n=12) and FO (n=12) had no influence on B-cell cytokines compared to baseline, and there were no differences in postintervention cytokine levels between treatment groups. Finally, ex vivo antibody levels were assayed with FO (n=7) after TLR9+BCR stimulation. Compared to baseline, FO lowered IgM but not IgG levels accompanied by select modifications to the plasma lipidome. Altogether, the results suggest that n-3 LC-PUFAs could modulate B-cell activity in humans, which will require further testing in a larger cohort. [ABSTRACT FROM AUTHOR]

N-3 polyunsaturated fatty acids (PUFAs) exert immunomodulatory effects on B cells. We previously demonstrated that n-3 PUFAs enhanced the relative percentage and/or frequency of select B2 cell subsets. The objectives here were to determine if n-3 PUFAs (a) could boost cytokines that target B-cell frequency, (b) enhance the frequency of the B1 population and (c) to identify the mechanism by which n-3 PUFAs modify the proportion of B cells. Administration of n-3 PUFAs as fish oil to C57BL/6 mice enhanced secretion of the Th2 cytokine IL-5 but not IL-9 or IL-13. N-3 PUFAs had no influence on the percentage or frequency of peritoneal B1 or B2 cells. Subsequent experiments with IL-5(-/-) knockout mice showed n-3 PUFAs decreased the percentage of bone marrow B220(lo)IgM(hi) cells and increased the proportion and number of splenic IgM(+)IgD(lo)CD21(lo) cells compared to the control. These results, when compared with our previous findings with wild-type mice, suggested IL-5 had no role in mediating the effect of n-3 PUFAs on B-cell populations. To confirm this conclusion, we assayed IL-5 secretion in a diet-induced obesity model in which n-3 PUFAs enhanced the frequency of select B-cell subsets. N-3 PUFA supplementation as ethyl esters to obesogenic diets did not alter circulating IL-5 levels. Altogether, the data establish that n-3 PUFAs as fish oil can increase circulating IL-5 in lean mice, which has implications for several disease end points, but this increase in IL-5 is not the mechanistic link between n-3 PUFAs and changes in B-cell populations. [ABSTRACT FROM AUTHOR]

We previously reported that docosahexaenoic-acid (DHA)-enriched fish oil (DFO) feeding altered B-cell membrane organization and enhanced B-cell function. The purpose of this study was to evaluate whether menhaden oil (MO) and eicosapentaenoic-acid (EPA)-enriched fish oil (EFO) alters B-cell function/phenotype similarly. Mice were fed control (CON), MO, EFO or DFO diets for 5 weeks. We evaluated the fatty acid composition of B-cell phospholipids, membrane microdomain organization, ex vivo B-cell functionality and in vivo B-cell subsets. Red blood cells and B cells were found to be strongly ( r >0.85) and significantly ( P <.001) correlated for major n-3 and n-6 long-chain polyunsaturated fatty acids (LCPUFAs). Compared to CON, MO and DFO resulted in decreased clustering of membrane microdomains, whereas EFO increased clustering. All fish oil treatments had 1.12–1.60 times higher CD40 expression following stimulation; however, we observed 0.86 times lower major histocompatibility complex class II expression and 0.7 times lower interleukin (IL)-6 production from EFO, but 3.25 times higher interferon-γ from MO and 1.5 times higher IL-6 from DFO. By 90 min of incubation, MO had 1.11 times higher antigen uptake compared to CON, whereas EFO was 0.86 times lower. All fish oil treatments resulted in decreasingly mature splenic and bone marrow B-cell subsets. We conclude that diets high in n-3 LCPUFAs may elicit similar B-cell phenotypes but different organizational and functional outcomes. More specifically, these data suggest that the EPA and DHA content of a diet influences immunological outcomes, highlighting the importance of understanding how specific n-3 LCPUFAs modulate B-cell development and function. [ABSTRACT FROM AUTHOR]