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.
Obesity is associated with increased risk for infections and poor responses to vaccinations, which may be due to compromised B cell function. However, there is limited information about the influence ...of obesity on B cell function and underlying factors that modulate B cell responses. Therefore, we studied B cell cytokine secretion and/or Ab production across obesity models. In obese humans, B cell IL-6 secretion was lowered and IgM levels were elevated upon ex vivo anti-BCR/TLR9 stimulation. In murine obesity induced by a high fat diet, ex vivo IgM and IgG were elevated with unstimulated B cells. Furthermore, the high fat diet lowered bone marrow B cell frequency accompanied by diminished transcripts of early lymphoid commitment markers. Murine B cell responses were subsequently investigated upon influenza A/Puerto Rico/8/34 infection using a Western diet model in the absence or presence of docosahexaenoic acid (DHA). DHA, an essential fatty acid with immunomodulatory properties, was tested because its plasma levels are lowered in obesity. Relative to controls, mice consuming the Western diet had diminished Ab titers whereas the Western diet plus DHA improved titers. Mechanistically, DHA did not directly target B cells to elevate Ab levels. Instead, DHA increased the concentration of the downstream specialized proresolving lipid mediators (SPMs) 14-hydroxydocosahexaenoic acid, 17-hydroxydocosahexaenoic acid, and protectin DX. All three SPMs were found to be effective in elevating murine Ab levels upon influenza infection. Collectively, the results demonstrate that B cell responses are impaired across human and mouse obesity models and show that essential fatty acid status is a factor influencing humoral immunity, potentially through an SPM-mediated mechanism.
Cardiolipin (CL) is a key phospholipid of the mitochondria. A loss of CL content and remodeling of CL's acyl chains is observed in several pathologies. Strong shifts in CL concentration and acyl ...chain composition would presumably disrupt mitochondrial inner membrane biophysical organization. However, it remains unclear in the literature as to which is the key regulator of mitochondrial membrane biophysical properties. We review the literature to discriminate the effects of CL concentration and acyl chain composition on mitochondrial membrane organization. A widely applicable theme emerges across several pathologies, including cardiovascular diseases, diabetes, Barth syndrome, and neurodegenerative ailments. The loss of CL, often accompanied by increased levels of lyso-CLs, impairs mitochondrial inner membrane organization. Modest remodeling of CL acyl chains is not a major driver of impairments and only in cases of extreme remodeling is there an influence on membrane properties.
•Cardiolipin (CL) is a unique mitochondrial phospholipid.•In many diseases, CL levels are decreased and CL acyl chains are remodeled.•Alterations to CL are associated with aberrant mitochondrial structure-function.•Loss of CL content often impairs inner mitochondrial membrane properties.•Only extreme CL acyl chain remodeling influences mitochondrial membrane properties.
Dietary supplementation with polyunsaturated fatty acids (PUFAs), especially those of the n-3 class, has immunosuppressive effects on both innate and adaptive immunity through various mechanisms. In ...this review, we focus on the PUFA modulation of membrane architecture and its consequent effects on both T cell responses and antigen presentation. We first use data from in vitro and in vivo experiments to make the case that the immunosuppressive effects of PUFAs begin with membrane incorporation and modulation of lipid-protein lateral organization. This in turn inhibits downstream signaling mediated by T cell receptors and suppresses T cell activation and proliferation. Next, we review evidence for PUFA-mediated alteration of major histocompatibility complex class I and II surface expression and antigen presentation. We propose that PUFAs influence the expression of major histocompatibility complex by altering its conformation, orientation, lateral organization, and trafficking, with consequences for recognition by effector T cells. Finally, we present data from model membrane studies to explain the physical principles that make PUFA acyl chains unique in modifying membrane lateral organization and protein function. An important concept to emerge from these studies is that PUFA acyl chains and cholesterol molecules are sterically incompatible. By applying this concept to the T cell activation and signaling model, mechanisms emerge by which PUFAs can modulate membrane lipid-protein lateral organization. Our data-based models show that membrane modification of both effectors and targets is an important, often overlooked, mechanism of immunomodulation by PUFAs.
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.
Diet‐induced obesity is associated with impaired B‐cell‐driven humoral immunity, which coincides with chronic inflammation and has consequences for responses to infections and vaccinations. Key ...nutritional, cellular, and molecular mechanisms by which obesity may impair aspects of humoral immunity such as B cell development, class switch recombination, and formation of long‐lived antibody secreting cells are reviewed. A key theme to emerge is the central role of white adipose tissue on the formation and function of pro‐inflammatory B cell subsets that exacerbate insulin resistance. The underlying role of select hormones such as leptin is highlighted, which may be driving the formation of pro‐inflammatory B cells in the absence of antigen stimulation. This review also extensively covers the regulatory role of lipid metabolites such as prostaglandins and specialized pro‐resolving mediators (SPMs) that are synthesized from polyunsaturated fatty acids. Notably, SPM biosynthesis is impaired in obesity and contributes toward impaired antibody production. Future directions for research, including avenues for therapeutic intervention, are included.
This review covers experimental data on how obesity impairs key aspects of humoral immunity. Notably, results from human and rodent studies suggest that leptin may be driving B lymphocytes to become pro‐inflammatory and secrete auto‐antibodies. The review also discusses how metabolites derived from polyunsaturated fatty acids regulate antigen‐specific antibody levels.
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.
DHA‐derived mediators increase select B cell subset numbers and lower circulating pathogenic IgG2c in obese male mice.
•Recent meta-analyses suggest that EPA is protective in major depression.•While EPA levels are low in the brain, it rapidly enters and is metabolised in the brain.•A better understanding of EPA ...metabolism in the brain could lead to new treatments for depression.
The results of several meta-analyses suggest that eicosapentaenoic acid (EPA) supplementation is therapeutic in managing the symptoms of major depression. It was previously assumed that because EPA is extremely low in the brain it did not cross the blood-brain barrier and any therapeutic effects it exerted would be via the periphery. However, more recent studies have established that EPA does enter the brain, but is rapidly metabolised following entry. While EPA does not accumulate within the brain, it is present in microglia and homeostatic mechanisms may regulate its esterification to phospholipids that serve important roles in cell signaling. Furthermore, a variety of signaling molecules from EPA have been described in the periphery and they have the potential to exert effects within the brain. If EPA is confirmed to be therapeutic in major depression as a result of adequately powered randomized clinical trials, future research on brain EPA metabolism could lead to the discovery of novel targets for treating or preventing major depression.
Menopause results in a progressive decline in 17β-estradiol (E2) levels, increased adiposity, decreased insulin sensitivity, and a higher risk for type 2 diabetes. Estrogen therapies can help reverse ...these effects, but the mechanism(s) by which E2 modulates susceptibility to metabolic disease is not well understood. In young C57BL/6N mice, short-term ovariectomy decreased—whereas E2 therapy restored—mitochondrial respiratory function, cellular redox state (GSH/GSSG), and insulin sensitivity in skeletal muscle. E2 was detected by liquid chromatography-mass spectrometry in mitochondrial membranes and varied according to whole-body E2 status independently of ERα. Loss of E2 increased mitochondrial membrane microviscosity and H2O2 emitting potential, whereas E2 administration in vivo and in vitro restored membrane E2 content, microviscosity, complex I and I + III activities, H2O2 emitting potential, and submaximal OXPHOS responsiveness. These findings demonstrate that E2 directly modulates membrane biophysical properties and bioenergetic function in mitochondria, offering a direct mechanism by which E2 status broadly influences energy homeostasis.
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•E2 restores redox balance and insulin sensitivity in skeletal muscle after ovariectomy•E2 localizes to mitochondria independently of ERα and lowers membrane microviscosity•E2 promotes bioenergetic function through complex I activity, electron transfer, and OXPHOS responsiveness•The fine-tuning effect of E2 in mitochondria influences energy homeostasis
Loss of estrogen from menopause increases the risk of developing metabolic diseases. Torres et al. show that 17β-estradiol (E2) localizes to mitochondrial membranes consistent with whole-body E2 status. The presence of E2 decreases microviscosity, which improves bioenergetic function, thus offering a biophysical mechanism by which E2 influences energy homeostasis.
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