The term immunometabolism has been coined to describe a bidirectional relationship between immune and metabolic activity; cellular metabolism drives the fate of an immune cell, and inflammatory/immune signals can cause profound metabolic shifts. An editorial recently published in Frontiers in Immunology highlights the role of immunometabolism in autoimmune disease, oncology, infectious disease, as well as systemic metabolism and compromised inflammatory responses driven by obesity, and briefly discusses recent advances in understanding the molecular mechanisms underlying immunometabolism. For instance, the distinction between pro-inflammatory M1 macrophages, which rely on glycolysis and produce reactive oxygen species, vs. M2 macrophages that are more dependent on fatty acid oxidation, the TCA cycle, and oxidative phosphorylation (and are involved in the resolution of inflammation and tissue repair), has implications for metabolic and cardiovascular health as well as oncology, as macrophage function influences many different types of diseases.
Lipids, particularly omega-3 fatty acids, play a key role in immunometabolism and immunomodulation. The journal Immunology & Cell Biology recently published a review of the lipid-immune system relationship, describing the role of lipids as key regulators of immune activation, differentiation, and homeostasis, with derivatives of long-chain polyunsaturated fatty acids (PUFAs), including eicosanoids and specialized pro-resolving mediators (SPMs), being among the most significant lipid regulators. More than simply a component of the lipid bilayer of cellular membranes, lipids act as cell signaling molecules, regulating immune cell function, recruiting leukocytes, assisting in phagocytosis, providing the structural basis (lipid rafts) for immune receptors, etc. SPMs specifically seem to target the resolution phase of the inflammatory process, and it is quite likely that much of the link between cellular metabolism and immune function is mediated by the presence (or absence) of a persistent suboptimal inflammatory response.
Among the most well-studied effects of lipid modulation of immune function may be related to macrophage activity, particularly the effect on inflammation and macrophage polarization, and it’s difficult to overestimate the effect of macrophage functionality on various human diseases. Tissue-resident macrophages (such as Langerhans cells in the skin, Kupffer cells in the liver, microglia in the central nervous system, alveolar macrophages in the lungs, etc.) “...are now recognized as central orchestrators of immunity, tissue homeostasis, and disease pathogenesis,” as reviewed recently in the journal MedComm. Lipids, particularly polyunsaturated lipids (omega-3s and 6s), and SPMs are potent modulators of macrophage function, driving the shift between a proinflammatory (M1-like) or anti-inflammatory (M2-like) state.
In a multi-omic analysis of omega-3/omega-6 modulation of macrophage activity, supplementation (in vitro) with these fatty acids was found to differentially reprogram the proteome, lipidome, and metabolome, with omega-3s strongly upregulating the activity of multiple enzymes involved in the inflammatory process and oxidative stress, including tyrosine-protein kinase CSK and catalase. Tyrosine-protein kinase CSK downregulates multiple pro-inflammatory signals, including interleukin-6 and TNF-α, while catalase not only detoxifies hydrogen peroxide, but it also downregulates NF-κB activity in macrophages, a key regulator of the inflammatory process as well as macrophage polarization. Omega-6 supplementation, in contrast, downregulated the activity of proteins (aspartate aminotransferase, fumarate hydratase, and isocitrate dehydrogenase), leading to changes in the concentrations of important cellular signals, including increases in succinate and fumarate and decreases in α-ketoglutarate. The net effect of elevations in succinate in fumarate is a stabilization of hypoxia-inducible factor 1α (HIF-1α), associated with increased inflammatory activity (interleukin-1β) and M1 macrophage polarization.
The normal transition from inflammation to resolution in macrophages is primarily mediated by SPMs, metabolites of the omega-3 fatty acids, that promote the M2 macrophage state. SPMs include resolvins (Rvs), containing the E-series derived from EPA and the D-series from DHA, as well as protectins (PDs) and maresins (MaRs), which are derivatives of DHA.
For example, RvD1 (a D-series resolvin) is one of the most well-studied SPMs. It suppresses NF-κB, enhances macrophage phagocytosis, and promotes the clearance of inflammatory cells and debris. In preclinical studies, it has been shown to promote the resolution phase of the inflammatory process (distinct from the inhibition of inflammation) in diverse conditions. RvD1 appears to play a prominent role in cardiovascular health, including atrial fibrillation, where it may prevent cardiac remodeling, and post-myocardial infarction, where it promotes the resolution of acute inflammation. In a recently published human study, serum levels of RvD1 were inversely associated (and independently predicted) with the risk of MACE (major adverse cardiovascular events) in a population at high risk (hemodialysis patients). RvD1 was also inversely associated with diabetes history, cardiac troponin T, and high-sensitivity C-reactive protein (CRP) in this same population.
In models of obesity and metabolic disease, RvD1 dose-dependently reduced inflammatory mediators in adipocytes, in part by polarizing macrophages to an anti-inflammatory (M2) phenotype, and also improved insulin resistance associated with a compromised inflammatory response induced via obesity. It appears to play a role in multiple models of autoimmune disease; for example, in models of rheumatoid arthritis, RvD1 has been shown to support a proper inflammatory response (by modulating microRNA expression), and among people with rheumatoid arthritis, serum levels were significantly lower compared to healthy controls (RvE1 levels were also significantly decreased). Among people with Hashimoto’s thyroiditis, not only were RvD1 levels lower than those of controls, but they were also inversely associated with thyroid peroxidase antibody levels and a number of inflammatory mediators.
SPMs have also been tied to respiratory health and allergy issues. RvD1, for example, helps resolve the airway’s natural inflammatory response in asthma by promoting eosinophil and neutrophil apoptosis, preventing an excessive airway response, and also inhibiting the change from IgG to IgE, the predominant immunoglobulin in allergic asthma. Resolvins also appear to play a role in intestinal repair; for example, in one model of the gut epithelial barrier in early life, although a cocktail of SPMs (lipoxin A4, RvD1, and RvE1) did not alter bacterial product-induced epithelial inflammation, they did significantly increase the recovery after injury. Other models also suggest that RvD1 protects against NSAID-induced epithelial injury, and similarly, RvE1 promotes natural epithelial wound repair by increasing cell migration/proliferation. Patients with IBS-C have lower RvD1 and higher CRP levels compared to controls (which may be a biomarker of IBS-C), with RvD1 levels inversely associated with abdominal pain.
The SPMs exert many of their physiological effects through selective G protein-coupled receptors. For example, RvD1 binds to GPR32, promoting the resolution of the natural inflammatory process through multiple mechanisms, including the induction of Foxp3+ Tregs (which tamp down the inflammatory response and neutrophil recruitment), downregulation of inflammatory miRNAs, inhibition of Toll-like receptors, etc.
In experimental models of liver disease, activation of G protein-coupled receptors by RvD1 (including GPR32 and formyl peptide receptor 2, FPR2) has many downstream effects that lead to reduced inflammation, oxidative stress, and improved mitochondrial function. This includes inhibition of MAPK, NF-κB, and JAK signaling, as well as upregulation of Nrf2 and antioxidant enzymes such as NQO1, superoxide dismutase, and glutathione. In addition, activation of G protein-coupled receptors upregulates the TRX2 signaling pathway, thereby promoting mitochondrial autophagy and restoring mitochondrial function. The downstream effects of this include increased adiponectin expression, improved glucose tolerance, reduced hepatic triglyceride and inflammatory biomarker (IL-6) levels. Human studies also reflect the preclinical models; individuals with non-alcoholic fatty liver disease (NAFLD) have been found to have reduced levels of RvD1 along with other indicators of increased oxidative stress and inflammation. Interestingly, a 12-month lifestyle intervention with the Mediterranean diet improved many of these biomarkers, including RvD1 levels, among people with NAFLD.
Multiple other SPMs appear key to the resolution of the body’s inflammatory response. For example, protectins, especially protectin D1 (PD1, derived from DHA and also called neuroprotection D1 or NPD1), have a growing evidence base for their role in inflammation resolution. Deficiency or dysregulation of NPD1 specifically has been implicated in neurodegenerative disease, including Alzheimer’s, Parkinson’s, and stroke. In a recent review published in Current Neuropharmacology, the authors conclude that NPD1’s “potential as a powerful anti-inflammatory, antioxidant, anti-amyloidogenic, and anti-apoptotic agent makes it a promising candidate for therapeutic applications.” Again, many of its actions are mediated via G protein-coupled receptors (including GPR32 and GPR37), with downstream effects such as suppression of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) and inhibition of the NF-κB pathway. GPR37, also known as parkin-associated endothelin-like receptor (Pael-R), may be a receptor specific for NPD1, and plays a pivotal role in promoting M2 macrophage polarization, linked to tissue repair and inflammation resolution. NPD1 also upregulates c-Rel, a transcription factor involved in immune regulation, and possibly melatonin production as well, itself an anti-inflammatory agent and antioxidant. NPD1 prevents the activation of microglia and astrocytes, associated with a neuroprotective effect.
In Alzheimer’s disease, NPD1 has special relevance, having been reported to be severely depleted in the Alzheimer’s brain. It is known to act as an anti-apoptotic agent that mitigates amyloid-beta (Aβ) toxicity (and toxicity from other malformed protein complexes). NPD1 also promotes the processing of amyloid precursor protein (APP), thereby resolving neural inflammation and decreasing Aβ42 levels. NPD1 also dose-dependently activates peroxisome proliferator-activated receptor-γ (PPAR-γ), which in turn has anti-inflammatory effects and reduces Aβ levels.
There is also some evidence that NPD1 plays a role in relieving neuropathic and chronic pain, at least partly mediated through the GPR37 receptor. This has been shown in an experimental model of chemotherapy-induced pain, as well as a model of pain associated with bone cancer. At least part of the mechanism may be increased production of IL-10 by macrophages, a prominent anti-inflammatory cytokine which also inhibits osteoclastogenesis, in response to GPR37 activation. It appears likely that pain relief may be a consequence of SPM activity in general, given the close correlation between pain and inflammatory compounds. For example, in a randomized and double-blind placebo-controlled trial published in the Journal of Translational Medicine, a significant reduction in pain was observed at 8 and 12 weeks among people with osteoarthritis of the knee when supplemented with an SPM combination (18-HEPE, 17-HDHA, and 14-HDHA), along with improvement in all 5 aspects of a quality of life scale (EUROQoL-5). Note that 18-HEPE is the precursor to the E-series resolvins, 17-HDHA to the D-series resolvins and protectins, and 14-HDHA to the maresins.
Among the maresins, Maresin 1 (MaR1) has received the most attention, primarily for an analgesic effect across a spectrum of pain models, including inflammatory, neuropathic, postoperative, osteoarthritis-related pain. Similar to other SPMs, MaR1 has been shown to polarize macrophages toward the M2 phenotype, downregulating production of pro-inflammatory cytokines (TNF-α, IL-1β) and inhibiting the activation of NF-κB. In vitro it has also demonstrated neuroprotective and regenerative effects, including promotion of the growth of dorsal root ganglion axons. MaR1 is speculated to act as an “off-switch” for glial activation associated with the release of pro-nociceptive mediators. It may also help to restore homeostasis; in one model this was characterized by an acceleration of glutamate clearance from the synaptic cleft following peripheral nerve injury, mediated by activation of what may be a receptor specific to MaR1, G-protein-coupled receptor 37-like 1 (GPR37L1). In a model of multiple sclerosis, MaR1 had diverse immunological benefits, including reducing neurological impairment and slowing disease development via a reduction in immune cell filtration into the central nervous system. It increased IL-10 production in both macrophages and CD4+ cells, and repaired the metabolic dysregulation within these same cell types (as well as microglia). It restored defective efferocytosis (phagocytic consumption of apoptotic cells) and preserved myelin. MaR1 has broad potential benefits for pain, resolution of the inflammatory process, and neuroprotection in preclinical models, but lacks human trials. In one recent study, plasma MaR1 and RvD1) levels were found to be lower among people with active ulcerative colitis (UC) compared to controls and also lower in people in remission compared to controls, suggesting its use as a possible biomarker for disease activity. Supplementation with SPM precursors (18- (HEPE), 14-HDHA, and 17-HDHA) has been shown to increase plasma levels of MaR1, but other outcomes of supplementation have not been studied.
EPA and DHA have long been studied for their immunomodulating effects, some of which are likely to be mediated by their metabolites (e.g., SPMs), but many are likely direct effects of these two essential fatty acids. For example, DHA treatment in polymorphonuclear leukocytes (PMN) cells promotes PPAR-γ activation, and in monocytes DHA inhibits TLR4 signaling, both effects leading to healthy support of the inflammatory process. Other mechanisms (reviewed here) include a reduction in NF-κB activation, induction of Nrf2 signaling, modulation of Wnt/beta-catenine pathways, reduced macrophage activity in atherosclerotic plaques, as well as limiting T cell proliferation and promoting their development into regulatory T cells (Treg), preventing an excessive immune response. EPA and DHA have distinct effects in each immune cell type, including macrophages, mast cells, peripheral blood mononuclear cells, natural killer cells, etc. (reviewed here).
Substantial research and clinical evidence also exist for EPA/DHA. For example, an umbrella review of 32 meta-analyses published in International Immunopharmacology found that omega-3 supplementation was associated with significant reductions in key inflammatory biomarkers, including serum C-reactive protein, tumor necrosis factor α, and interleukin 6 concentrations under a variety of health conditions, and “can be recommended as adjuvant anti-inflammatory agents.” The journal Frontiers in Medicine recently published a systematic review and meta-analysis of 41 randomized and controlled trials evaluating omega-3 fatty acid supplementation for chronic pain. They found a clinically significant reduction in pain by 1 month of supplementation, improved by 6 months, with significant benefits for rheumatoid arthritis, migraine, and other mixed chronic pain conditions.
In a large double-blind and placebo-controlled trial of vitamin D and/or omega-3 fatty acid supplementation for autoimmune disease (Vitamin D and Omega-3 Trial, VITAL), initial results found that omega-3s reduced the incidence of autoimmune disease development 15%, but this was not a significant reduction. However, the journal Arthritis & Rheumatology published an analysis that followed participants (over 21,000) for an additional 2 years after the study ended, and they found that the group receiving omega-3s had a 17% reduction in the incidence of autoimmune disease, which was statistically significant. It’s worth noting that a recent analysis of the National Health and Nutrition Examination Survey (NHANES) 1999-2004 data found that among people self-reporting arthritis, those in the highest tertile of omega-3 fatty acid intake had a 57% lower risk of autoantibody (ANA) positivity compared to the lowest tertile, and no association was observed for other fatty acids.
DHA/EPA also supports mitochondrial function, which has meaningful effects on immune activity. In a small case-control study published in the Journal of Nutritional Biochemistry, a number of bioenergetic markers (e.g., proton leak, nonmitochondrial respiration, basal ATP production, etc.) were different when compared in the peripheral blood mononuclear cells of women with grade II obesity compared to lean controls. Similarly, multiple immune markers (Th1, Th2, Th17, CD4+ Tregs, CD8+ Tregs, Bregs, M1 monocytes, and pDCreg cells) were higher among the women with obesity compared to controls. Supplementation with DHA/EPA improved mitochondrial bioenergetics markers and influenced peripheral pro-inflammatory and anti-inflammatory lymphocyte and monocytes within 1 month of supplementation, suggesting that omega-3s may help improve mitochondrial function and modulate the inflammatory response which often underlies obesity.
Collectively, there is now robust evidence for the mechanisms by which omega-3s, including DHA/EPA as well as SPMs, modify immune function. In addition to playing structural roles, these bioactive compounds enhance mitochondrial function, activate key immune functions and cells, most notably the polarization of macrophages, and target the resolution of the inflammatory process (thereby promoting homeostasis), which drives many acute and chronic conditions.
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