Microbiome-derived bacterial lipids regulate gene expression of proinflammatory pathway inhibitors in systemic monocytes.

How the microbiome regulates responses of systemic innate immune cells is unclear. In the present study, our purpose was to document a novel mechanism by which the microbiome mediates crosstalk with the systemic innate immune system. We have identified a family of microbiome Bacteroidota-derived lipopeptides-the serine-glycine (S/G) lipids, which are TLR2 ligands, access the systemic circulation, and regulate proinflammatory responses of splenic monocytes. To document the role of these lipids in regulating systemic immunity, we used oral gavage with an antibiotic to decrease the production of these lipids and administered exogenously purified lipids to increase the systemic level of these lipids. We found that decreasing systemic S/G lipids by decreasing microbiome Bacteroidota significantly enhanced splenic monocyte proinflammatory responses. Replenishing systemic levels of S/G lipids via exogenous administration returned splenic monocyte responses to control levels. Transcriptomic analysis demonstrated that S/G lipids regulate monocyte proinflammatory responses at the level of gene expression of a small set of upstream inhibitors of TLR and NF-κB pathways that include Trem2 and Irf4. Consistent with enhancement in proinflammatory cytokine responses, decreasing S/G lipids lowered gene expression of specific pathway inhibitors. Replenishing S/G lipids normalized gene expression of these inhibitors. In conclusion, our results suggest that microbiome-derived S/G lipids normally establish a level of buffered signaling activation necessary for well-regulated innate immune responses in systemic monocytes. By regulating gene expression of inflammatory pathway inhibitors such as Trem2, S/G lipids merit broader investigation into the potential dysfunction of other innate immune cells, such as microglia, in diseases such as Alzheimer's disease.

IL-10 Differentially Promotes Mast Cell Responsiveness to IL-33, Resulting in Enhancement of Type 2 Inflammation and Suppression of Neutrophilia.

Mast cells (MCs) play critical roles in the establishment of allergic diseases. We recently demonstrated an unexpected, proinflammatory role for IL-10 in regulating MC responses. IL-10 enhanced MC activation and promoted IgE-dependent responses during food allergy. However, whether these effects extend to IgE-independent stimuli is not clear. In this article, we demonstrate that IL-10 plays a critical role in driving IL-33-mediated MC responses. IL-10 stimulation enhanced MC expansion and degranulation, ST2 expression, IL-13 production, and phospho-relA upregulation in IL-33-treated cells while suppressing TNF-α. These effects were partly dependent on endogenous IL-10 and further amplified in MCs coactivated with both IL-33 and IgE/Ag. IL-10's divergent effects also extended in vivo. In a MC-dependent model of IL-33-induced neutrophilia, IL-10 treatment enhanced MC responsiveness, leading to suppression of neutrophils and decreased TNF-α. In contrast, during IL-33-induced type 2 inflammation, IL-10 priming exacerbated MC activity, resulting in MC recruitment to various tissues, enhanced ST2 expression, induction of hypothermia, recruitment of eosinophils, and increased MCPT-1 and IL-13 levels. Our data elucidate an important role for IL-10 as an augmenter of IL-33-mediated MC responses, with implications during both allergic diseases and other MC-dependent disorders. IL-10 induction is routinely used as a prognostic marker of disease improvement. Our data suggest instead that IL-10 can enhance ST2 responsiveness in IL-33-activated MCs, with the potential to both aggravate or suppress disease severity depending on the inflammatory context.

The Role of Lipids in the Regulation of Immune Responses.

Lipid metabolism plays a major role in the regulation of the immune system. Exogenous (dietary and microbial-derived) and endogenous (non-microbial-derived) lipids play a direct role in regulating immune cell activation, differentiation and expansion, and inflammatory phenotypes. Understanding the complexities of lipid-immune interactions may have important implications for human health, as certain lipids or immune pathways may be beneficial in circumstances of acute infection yet detrimental in chronic inflammatory diseases. Further, there are key differences in the lipid effects between specific immune cell types and location (e.g., gut mucosal vs. systemic immune cells), suggesting that the immunomodulatory properties of lipids may be tissue-compartment-specific, although the direct effect of dietary lipids on the mucosal immune system warrants further investigation. Importantly, there is recent evidence to suggest that lipid-immune interactions are dependent on sex, metabolic status, and the gut microbiome in preclinical models. While the lipid-immune relationship has not been adequately established in/translated to humans, research is warranted to evaluate the differences in lipid-immune interactions across individuals and whether the optimization of lipid-immune interactions requires precision nutrition approaches to mitigate or manage disease. In this review, we discuss the mechanisms by which lipids regulate immune responses and the influence of dietary lipids on these processes, highlighting compelling areas for future research.

Effects of Milk Polar Lipids on DSS-Induced Colitis Severity Are Dependent on Dietary Fat Content.

In the United States, over three million adults suffer from inflammatory bowel disease (IBD). The gut microbiome, host immune response, and nutrient-microbial interactions are known to play a role in IBD. The relationship between dairy and IBD is controversial; thus, the objectives of this study were to identify how milk polar lipids (MPLs) and anhydrous milk fat affect colitis disease activity, the colonic transcriptome, and the gut microbiome in a mouse model of chemical-induced colitis. Male and female C57BL/6J mice (n = 120) were randomized into either a low (5% w/w) milk fat or a high (21% w/w) milk fat diet supplemented with either 0%, 1%, or 2% w/w of MPLs for three weeks (n = 10/group/sex). Afterwards, colitis was induced using 1% dextran sodium sulfate in drinking water for five days (colitis induction) and then switched to regular water for five days (colitis recovery). Mice fed added MPLs were protected against colitis when fed a high-fat diet, while added MPLs during low-fat diet attenuated disease activity during the colitis induction period yet promoted colitis and inflammation in male mice during the recovery period. Dietary fat content can alter colitis and influence the anti-inflammatory effect of milk polar lipids.

Dietary Influences on Gut Microbiota with a Focus on Metabolic Syndrome.

There is a clear correlation between gut microbiota, diet, and metabolic outcomes. A diet high in fiber has been shown to decrease inflammation, increase insulin sensitivity, and reduce dyslipidemias whereas a diet high in fat and sugar leads to dyslipidemia, insulin resistance, and low-grade inflammation. There is recent evidence suggesting that the human gut microbiota has a significant role in the development or the resolution of metabolic syndrome (MetS) and associated conditions. Leading a stressful, sedentary lifestyle with limited or no physical activity and consuming an unhealthy diet high in saturated fat, simple carbohydrates, and sodium and low in dietary fiber and in high-quality protein are some of the contributing factors. Unhealthy diets have been shown to induce alterations in the gut microbiota and contribute to the pathogenesis of MetS by altering microbiota composition and disrupting the intestinal barrier, which leads to low-grade systemic inflammation. In contrast, healthy diets can lead to changes in microbiota that increase gut barrier function and increase the production of anti-inflammatory biomarkers. This review aims at providing a more in-depth discussion of diet-induced dysbiosis of the gut microbiota and its effect on MetS. Here, we discuss the possible mechanisms involved in the development of the metabolic biomarkers that define MetS, with an emphasis on the role of sugar and dietary fiber in microbiome-mediated changes in low-grade systemic inflammation and metabolic dysfunction.

The Effects of Eggs in a Plant-Based Diet on Oxidative Stress and Inflammation in Metabolic Syndrome.

We recently reported that the inclusion of whole eggs in plant-based diets (PBD) increased plasma choline, lutein, and zeaxanthin in individuals with metabolic syndrome (MetS). The objective of the current study was to evaluate whether this dietary pattern would protect against oxidative stress and low-grade inflammation, two common characteristics of MetS. We recruited 24 men and women with MetS, who, after following a PBD for 2 weeks (baseline), were randomly allocated to consume either two whole eggs with 70 g of spinach/day (EGG) or the equivalent amount of egg substitute with spinach (SUB) as breakfast for 4 weeks. After a 3-week washout, they were allocated to the alternate breakfast. We measured biomarkers of oxidation and inflammation at baseline and at the end of each intervention. Tumor necrosis factor-alpha, interleukin-6, monocyte protein attractant-1, liver enzymes, and C-reactive protein, as well as total antioxidant capacity, paraoxonase-1 (PON-1) activity, and other biomarkers of oxidation were not different at the end of EGG or SUB or when compared to baseline. However, plasma malondialdehyde (MDA) concentrations were lower (p < 0.05) during the EGG and baseline compared to SUB. In addition, the increases in dietary lutein and zeaxanthin previously observed had a strong positive correlation with PON-1 activity (r = 0.522, p < 0.01) only during the EGG period, whereas plasma zeaxanthin was negatively correlated with MDA (r = −0.437, p < 0.01). The number of participants with MetS was reduced from 24 during screening to 21, 13, and 17 during the BL, EGG, and SUB periods, respectively, indicating that eggs were more effective in reversing the characteristics of MetS. These data suggest that adding eggs to a PBD does not detrimentally affect inflammation or oxidative stress; on the contrary, eggs seem to provide additional protection against the biomarkers that define MetS.

Comparison between Egg Intake versus Choline Supplementation on Gut Microbiota and Plasma Carotenoids in Subjects with Metabolic Syndrome.

We previously demonstrated that intake of three eggs/d for 4 weeks increased plasma choline and decreased inflammation in subjects with metabolic syndrome (MetS). The purpose of the current study was to further explore the effects of phosphatidylcholine (PC) provided by eggs versus a choline bitartrate (CB) supplement on the gut microbiota, trimethylamine N-oxide (TMAO) formation, and plasma carotenoids lutein and zeaxanthin in MetS. This randomized, controlled crossover clinical trial included 23 subjects with MetS. Following a washout period of 2 weeks without consuming any choline-containing foods, subjects were randomly allocated to consume either three eggs/d or a CB supplement for 4 weeks (both diets had a choline equivalent of 400 mg/day). DNA was extracted from stool samples to sequence the 16S rRNA gene region for community analysis. Operational taxonomic units (OTUs) and the α-diversity of the community were determined using QIIME software. Plasma TMAO, methionine, betaine, and dimethylglycine (DMG) were quantified by stable isotope dilution liquid chromatography with tandem mass spectrometry. Plasma carotenoids, lutein, and zeaxanthin were measured using reversed-phase high-performance liquid chromatography. There were significant increases in plasma lutein and zeaxanthin after egg intake compared to the baseline or intake of CB supplement (p < 0.01). In contrast, TMAO was not different between treatments compared to the baseline (p > 0.05). Additionally, while diet intervention had no effects on microbiota diversity measures or relative taxa abundances, a correlation between bacterial biodiversity and HDL was observed. Following egg intake, the observed increases in plasma lutein and zeaxanthin may suggest additional protection against oxidative stress, a common condition in MetS.

Interplay between diet, the gut microbiome, and atherosclerosis: Role of dysbiosis and microbial metabolites on inflammation and disordered lipid metabolism.

Atherosclerosis remains the leading cause of death worldwide. Lifestyle modification, including diet and exercise, is recommended to be the primary prevention strategy for atherosclerosis. Dietary patterns have been shown to be strongly associated with atherosclerosis risk. In addition, diet-induced modulation of gut microbiota and the resultant microbial metabolites may influence the progression of atherosclerosis. This review summarizes the role of gut dysbiosis and different microbial metabolites in atherosclerosis, and how different diets may promote or prevent atherosclerosis through gut microbiome modulation. Non-digestible carbohydrates can increase the production of microbial metabolite short-chain fatty acids in the gut, protecting the gut barrier and decreasing overall systemic inflammation. High animal protein/L-carnitine diets may contribute to gut microbiome-dependent production of trimethylamine N-oxide, contributing to atherosclerosis by increased foam cell formation, decreased reverse cholesterol transport (RCT), and pro-thrombotic actions. Western/high-fat diets can increase the gut microbiome production of secondary bile acids and influence downstream signaling via farnesoid X receptor and lead to dysbiosis. Dysbiosis leads to the translocation of lipopolysaccharide (LPS) to the bloodstream by compromising the gut barrier. LPS can activate Toll-like receptor 4 signaling and decrease RCT to exacerbate atherosclerosis. Studies showing a relationship between the gut microbiome and atherosclerosis are still mostly through correlation, while causal pathways are still being uncovered. Future research should integrate proteomics and metabolomics to 16S microbiome sequencing to get a complete picture of the pathways, metabolites, and microbes involved, and to elucidate the complex interaction between the gut microbiome and atherosclerosis.

Gut microbiome-derived glycine lipids are diet-dependent modulators of hepatic injury and atherosclerosis.

Oral and gut Bacteroidetes produce unique classes of serine-glycine lipodipeptides and glycine aminolipids that signal through host Toll-like receptor 2. These glycine lipids have also been detected in human arteries, but their effects on atherosclerosis are unknown. Here, we sought to investigate the bioactivity of bacterial glycine lipids in mouse models of atherosclerosis. Lipid 654 (L654), a serine-glycine lipodipeptide species, was first tested in a high-fat diet (HFD)-fed Ldlr-/- model of atherosclerosis. Intraperitoneal administration of L654 over 7 weeks to HFD-fed Ldlr-/- mice resulted in hypocholesterolemic effects and significantly attenuated the progression of atherosclerosis. We found that L654 also reduced liver inflammatory and extracellular matrix gene expression, which may be related to inhibition of macrophage activation as demonstrated in vivo by lower major histocompatibility complex class II gene expression and confirmed in cell experiments. In addition, L654 and other bacterial glycine lipids in feces, liver, and serum were markedly reduced alongside changes in Bacteroidetes relative abundance in HFD-fed mice. Finally, we tested the bioactivities of L654 and related lipid 567 in chow-fed Apoe-/- mice, which displayed much higher fecal glycine lipids relative to HFD-fed Ldlr-/- mice. Administration of L654 or lipid 567 for 7 weeks to these mice reduced the liver injury marker alanine aminotransferase, but other effects seen in Ldlr-/- were not observed. Therefore, we conclude that conditions in which gut microbiome-derived glycine lipids are lost, such as HFD, may exacerbate the development of atherosclerosis and liver injury, whereas correction of such depletion may protect from these disorders.

Cardiometabolic health benefits of dairy-milk polar lipids.

Low-quality dietary patterns impair cardiometabolic health by increasing the risk of obesity-related disorders. Cardiometabolic risk relative to dairy-food consumption continues to be a controversial topic, due to recommendations that endorse low-fat and nonfat dairy foods over full-fat varieties despite accumulated evidence that does not strongly support these recommendations. Controlled human studies and mechanistic preclinical investigations support that full-fat dairy foods decrease cardiometabolic risk by promoting gut health, reducing inflammation, and managing dyslipidemia. These gut- and systemic-level cardiometabolic benefits are attributed, at least in part, to milk polar lipids (MPLs) derived from the phospholipid- and sphingolipid-rich milk fat globule membrane that is of higher abundance in full-fat dairy milk. The controversy surrounding full-fat dairy food consumption is discussed in this review relative to cardiometabolic health and MPL bioactivities that alleviate dyslipidemia, shift gut microbiota composition, and reduce inflammation. This summary, therefore, is expected to advance the understanding of full-fat dairy foods through their MPLs and the need for translational research to establish evidence-based dietary recommendations.

Antioxidant properties of anthocyanins and their mechanism of action in atherosclerosis.

Atherosclerosis develops due to lipid accumulation in the arterial wall and sclerosis as result of increased hyperlipidemia, oxidative stress, lipid oxidation, and protein oxidation. However, improving antioxidant status through diet may prevent the progression of atherosclerotic cardiovascular disease. It is believed that polyphenol-rich plants contribute to the inverse relationship between fruit and vegetable intake and chronic disease. Anthocyanins are flavonoid polyphenols with antioxidant properties that have been associated with reduced risk of cardiovascular disease. The consumption of anthocyanins increases total antioxidant capacity, antioxidant defense enzymes, and HDL antioxidant properties by several measures in preclinical and clinical populations. Anthocyanins appear to impart antioxidant actions via direct antioxidant properties, as well as indirectly via inducing intracellular Nrf2 activation and antioxidant gene expression. These actions counter oxidative stress and inflammatory signaling in cells present in atherosclerotic plaques, including macrophages and endothelial cells. Overall, anthocyanins may protect against atherosclerosis and cardiovascular disease through their effects on cellular antioxidant status, oxidative stress, and inflammation; however, their underlying mechanisms of action appear to be complex and require further elucidation.

Milk Polar Lipids: Underappreciated Lipids with Emerging Health Benefits.

Milk fat is encased in a polar lipid-containing tri-layer milk fat globule membrane (MFGM), composed of phospholipids (PLs) and sphingolipids (SLs). Milk PLs and SLs comprise about 1% of total milk lipids. The surfactant properties of PLs are important for dairy products; however, dairy products vary considerably in their polar lipid to total lipid content due to the existence of dairy foods with different fat content. Recent basic science and clinical research examining food sources and health effects of milk polar lipids suggest they may beneficially influence dysfunctional lipid metabolism, gut dysbiosis, inflammation, cardiovascular disease, gut health, and neurodevelopment. However, more research is warranted in clinical studies to confirm these effects in humans. Overall, there are a number of potential effects of consuming milk polar lipids, and they should be considered as food matrix factors that may directly confer health benefits and/or impact effects of other dietary lipids, with implications for full-fat vs. reduced-fat dairy.

Divergent Roles of Inflammation in Skeletal Muscle Recovery From Injury.

A transient increase in local pro-inflammatory cytokine expression following skeletal muscle injury mediates the repair and regeneration of damaged myofibers through myogenesis. Regenerative capacity is diminished and muscle wasting occurs, however, when intramuscular inflammatory signaling is exceedingly high or persists chronically. An excessive and persistent inflammatory response to muscle injury may therefore impair recovery by limiting the repair of damaged tissue and triggering muscle atrophy. The concentration-dependent activation of different downstream signaling pathways by several pro-inflammatory cytokines in cell and animal models support these opposing roles of post-injury inflammation. Understanding these molecular pathways is essential in developing therapeutic strategies to attenuate excessive inflammation and accelerate functional recovery and muscle mass accretion following muscle damage. This is especially relevant given the observation that basal levels of intramuscular inflammation and the inflammatory response to muscle damage are not uniform across all populations, suggesting certain individuals may be more susceptible to an excessive inflammatory response to injury that limits recovery. This narrative review explores the opposing roles of intramuscular inflammation in muscle regeneration and muscle protein turnover. Factors contributing to an exceedingly high inflammatory response to damage and age-related impairments in regenerative capacity are also considered.

Cow's milk polar lipids reduce atherogenic lipoprotein cholesterol, modulate gut microbiota and attenuate atherosclerosis development in LDL-receptor knockout mice fed a Western-type diet.

Milk sphingomyelin (SM), a polar lipid (PL) component of milk fat globule membranes, is protective against dyslipidemia. However, it is unclear whether ingestion of milk PLs protect against atherosclerosis. To determine this, male LDLr-/- mice (age 6 weeks) were fed ad libitum either a high-fat, added-cholesterol diet (CTL; 45% kcal from fat, 0.2% cholesterol by weight; n=15) or the same diet supplemented with 1% milk PL (1% MPL; n=15) or 2% milk PL (2% MPL; n=15) added by weight from butter serum. After 14 weeks on diets, mice fed 2% MPL had significantly lower serum cholesterol (-51%) compared to CTL (P<.01), with dose-dependent effects in lowering VLDL- and LDL-cholesterol. Mice fed 2% MPL displayed lower inflammatory markers in the serum, liver, adipose and aorta. Notably, milk PLs reduced atherosclerosis development in both the thoracic aorta and the aortic root, with 2% MPL-fed mice having significantly lower neutral lipid plaque size by 59% (P<.01) and 71% (P<.02) compared to CTL, respectively. Additionally, the 2% MPL-fed mice had greater relative abundance of Bacteroidetes, Actinobacteria and Bifidobacterium, and lower Firmicutes in cecal feces compared to CTL. Milk PL feeding resulted in significantly different microbial communities as demonstrated by altered beta diversity indices. In summary, 2% MPL strongly reduced atherogenic lipoprotein cholesterol, modulated gut microbiota, lowered inflammation and attenuated atherosclerosis development. Thus, milk PL content may be important to consider when choosing dairy products as foods for cardiovascular disease prevention.

Protective properties of milk sphingomyelin against dysfunctional lipid metabolism, gut dysbiosis, and inflammation.

The identification of natural bioactive compounds aimed at promoting optimal gut health and improving lipid metabolism is paramount in the prevention of chronic disease. In this review, we summarize basic science and clinical research examining the protective properties of milk sphingomyelin (SM) against dysfunctional lipid metabolism, gut dysbiosis, and inflammation. Dietary SM dose-dependently reduces the intestinal absorption of cholesterol, triglycerides, and fatty acids in cell culture and rodent studies. Overall, rodent feeding studies show dietary milk SM, milk polar lipid mixtures, and milk fat globule membrane reduce serum and hepatic lipid concentrations. Furthermore, these hypolipidemic effects are observed in some supplementation studies in humans, although the extent of reductions in serum cholesterol is typically smaller and only one trial was conducted with purified SM. Dietary milk SM has been reported to affect the gut microbiota in rodent studies and its hydrolytic product, sphingosine, displays bactericidal activity in vitro. Milk SM may also improve gut barrier function to prevent the translocation of inflammatory gut bacteria-derived molecules. Current evidence from pre-clinical studies indicates that dietary milk SM has protective properties against dysfunctional lipid metabolism, gut dysbiosis, and inflammation. The hypolipidemic effects of milk SM observed in animal studies have been reported in some human studies, although the magnitude of such effects is typically smaller. More research is warranted to clearly define how dietary milk SM influences lipid metabolism, gut microbiota, and inflammation in humans.

Dietary Anthocyanins and Human Health.

Anthocyanins may contribute to the inverse relationship between fruit and vegetable intake and chronic disease. Anthocyanins are pigments found in plant structures that consist of an anthocyanidin (aglycone) attached to sugar moieties. Anthocyanins may be beneficial for health through effects on cellular antioxidant status and inflammation; however, their underlying mechanisms of action in their protection of chronic diseases are likely complex and require further elucidation. This Special Issue comprises 8 peer-reviewed papers (including 6 original research articles) which highlight the diverse bioactivities of anthocyanins and anthocyanin-rich foods in the protection against chronic disease.

Dietary Egg Sphingomyelin Prevents Aortic Root Plaque Accumulation in Apolipoprotein-E Knockout Mice.

Western-style diets have been linked with dyslipidemia and inflammation, two well-known risk factors associated with cardiovascular disease (CVD). Dietary sphingomyelin (SM) has been reported to modulate gut microbiota, and lower serum lipids and inflammation in mice on Western-style diets. However, few studies have examined if nutritionally-relevant intake of dietary SM can impact atherosclerosis progression. Thus, the aim of this study was to determine if incorporating 0.1% (w/w) egg SM (ESM) (equivalent to ~750 mg/day in humans) into a high-fat (45% kcal), cholesterol-enriched diet (HFD) could prevent atheroprogression in apoE-/- mice (n = 15/group). We found that mice fed with the ESM-rich diet had significantly lower epididymal fat mass (-46%) and tended to have higher spleen weights (+15%). There were no significant differences in serum lipids between groups. However, ESM-fed mice had significantly lower alanine aminotransferase (ALT) activity. Additionally, ESM-fed mice displayed significantly less aortic root lipid accumulation (-31%) compared to controls. This improvement in atherosclerosis was paired with over a two-fold reduction in circulating serum amyloid A (SAA) in ESM-fed mice. Finally, there was also a modulation of the gut microbiota with ESM supplementation. ESM may have the potential to prevent atherosclerosis, however further research in the clinical setting is warranted.

Macrophage plasticity, polarization and function in response to curcumin, a diet-derived polyphenol, as an immunomodulatory agent.

Monocytes and macrophages are important cells of the innate immune system that have diverse functions, including defense against invading pathogens, removal of dead cells by phagocytosis, antigen presentation in the context of MHC class I and class II molecules, and production of various pro-inflammatory cytokines and chemokines such as IL-1ß, IL-6, TNF-α and MCP-1. In addition, pro-inflammatory (M1) and anti-inflammatory (M2) macrophages clearly play important roles in the progression of several inflammatory diseases. Therefore, therapies that target macrophage polarization and function by either blocking their trafficking to sites of inflammation, or skewing M1 to M2 phenotype polarization may hold clinical promise in several inflammatory diseases. Dietary-derived polyphenols have potent natural anti-oxidative properties. Within this group of polyphenols, curcumin has been shown to suppress macrophage inflammatory responses. Curcumin significantly reduces co-stimulatory molecules and also inhibits MAPK activation and the translocation of NF-κB p65. Curcumin can also polarize/repolarize macrophages toward the M2 phenotype. Curcumin-treated macrophages have been shown to be highly efficient at antigen capture and endocytosis via the mannose receptor. These novel findings provide new perspectives for the understanding of the immunopharmacological role of curcumin, as well as its therapeutic potential for impacting macrophage polarization and function in the context of inflammation-related disease. However, the precise effects of curcumin on the migration, differentiation, polarization and immunostimulatory functions of macrophages remain unknown. Therefore, in this review, we summarized whether curcumin can influence macrophage polarization, surface molecule expression, cytokine and chemokine production and their underlying pathways in the prevention of inflammatory diseases.

Immune modulation by curcumin: The role of interleukin-10.

Cytokines are small secreted proteins released by different types of cells with specific effects on cellular signaling and communication via binding to their receptors on the cell surface. IL-10 is known to be a pleiotropic and potent anti-inflammatory and immunosuppressive cytokine that is produced by both innate and adaptive immunity cells including dendritic cells, macrophages, mast cells, natural killer cells, eosinophils, neutrophils, B cells, CD8+ T cells, and TH1, TH2, and TH17 and regulatory T cells. Both direct and indirect activation of the stress axis promotes IL-10 secretion. IL-10 deregulation plays a role in the development of a large number of inflammatory diseases such as neuropathic pain, Parkinson's disease, Alzheimer's disease, osteoarthritis, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, type 1 diabetes, inflammatory bowel disease, and allergy. Curcumin is a natural anti-inflammatory compound able to induce the expression and production of IL-10 and enhancing its action on a large number of tissues. In vitro and in pre-clinical models curcumin is able to modulate the disease pathophysiology of conditions such as pain and neurodegenerative diseases, bowel inflammation, and allergy, but also of infections and cancer through its effect on IL-10 secretion. In humans, at least one part of the positive effects of curcumin on health could be related to its ability to enhance IL-10 -mediated effects.