key: cord-0868900-v5jyr1x9
authors: Johnson, Wade T.; Dorn, Nicholas C.; Ogbonna, Dora A.; Bottini, Nunzio; Shah, Nisarg J.
title: Lipid‐based regulators of immunity
date: 2021-12-31
journal: Bioeng Transl Med
DOI: 10.1002/btm2.10288
sha: 5b4fe593d5dbf6989341feb1dbf78ce0c89c3142
doc_id: 868900
cord_uid: v5jyr1x9

Lipids constitute a diverse class of molecular regulators with ubiquitous physiological roles in sustaining life. These carbon‐rich compounds are primarily sourced from exogenous sources and may be used directly as structural cellular building blocks or as a substrate for generating signaling mediators to regulate cell behavior. In both of these roles, lipids play a key role in both immune activation and suppression, leading to inflammation and resolution, respectively. The simple yet elegant structural properties of lipids encompassing size, hydrophobicity, and molecular weight enable unique biodistribution profiles that facilitate preferential accumulation in target tissues to modulate relevant immune cell subsets. Thus, the structural and functional properties of lipids can be leveraged to generate new materials as pharmacological agents for potently modulating the immune system. Here, we discuss the properties of three classes of lipids: polyunsaturated fatty acids, short‐chain fatty acids, and lipid adjuvants. We describe their immunoregulatory functions in modulating disease pathogenesis in preclinical models and in human clinical trials. We conclude with an outlook on harnessing the diverse and potent immune modulating properties of lipids for immunoregulation.

Lipids, colloquially called fats, are nonpolar hydrocarbons that have a pleiotropic role in modulating physiological functions, including in energy storage, maintaining cell membrane integrity, and cell signaling. 1 Fatty acids (FAs) are a major class of lipids characterized by a hydrocarbon chain functionalized with a carboxylic acid. FAs are primarily sourced from exogenous sources, such as through dietary essential fatty acids (EFAs) and have been demonstrated to influence the immune response through cell signaling that directly and indirectly activate or suppress cells of both the innate (e.g., neutrophils) and adaptive (e.g., T cells and B cells) immune system. Some FAs are associated with inflammatory diseases and may serve as biomarkers for assessing progression, such as the pro-inflammatory metabolites of FA called eicosanoids, for chronic conditions such as rheumatoid arthritis, 2 asthma, 3 and inflammatory bowel disease (IBD). 4 In humans, the two principal immunoregulatory FAs are polyunsaturated fatty acids (PUFAs) and short-chain fatty acids (SCFAs), which together constitute about 15% of the total FAs content, with the remainder comprised of monounsaturated and saturated FAs. 5 PUFAs are characterized by multiple unsaturations (double bonds) in the lipid tail and follow a "ω-x" nomenclature, where "x" refers to the carbon atom with the first unsaturation on the aliphatic chain from the methyl terminus. The key structural difference between ω-3 and ω-6 PUFAs is in the location of a carbon double bond. This seemingly innocuous change has a significant effect on their metabolic derivatives (eicosanoids) which directly modulate immune cells. SCFAs are small molecule metabolites, comprising less than six carbon atoms with no unsaturations and are derived from the breakdown of complex carbohydrates by gut microbiota. 6 These products of bacterial fermentation follow the standard IUPAC naming system for carboxylic acids (e.g., propionate [three carbon atoms], butyrate [four carbon atoms]). By activating G-protein-coupled cell membrane receptors (GPCRs) and inhibiting histone deacetylase (HDAC), SCFAs can modulate the activity of regulatory immune cells.

Outside their structural role in maintaining cell membrane fluidity, extracellular PUFAs are found in tissue microenvironments and are relatively enriched as a fraction of total FA in the brain, heart, and blood plasma. 5 SCFAs diffuse from the gut lumen, which is the primary site for their biosynthesis, via a strong biological gradient and can partition in tissues throughout the body. At homeostasis, SCFA concentration in tissues outside the intestine is negligible, suggesting that SCFAs primarily affect cells associated with the lower gastrointestinal tract. 6 In this review, we will first describe the structural properties of PUFAs, their derivatives, and target signaling pathways, which leads to either activation of pro-inflammatory immune cells and inflammatory mediators or an anti-inflammatory effect that seeks to resolve inflammation. Next, we will describe the structure of SCFA and their dual role as signaling molecules and as epigenetic modulators of immune function, which have been harnessed in treating inflammatory diseases. We will then review lipids used as adjuvants, the immunostimulatory component that enhances the protective immune response to vaccines. We conclude with an outlook on harnessing the immunoregulatory properties of lipids to develop the next generation of immunomodulating medicines ( Figure 1 ).

The human diet comprises several types of PUFAs of which linoleic acid (ω-6 PUFA) and α-linoleic acid (ω-3 PUFA) are the most common. 7, 8 Linoleic acid is converted to arachidonic acid (ARA, 20:4ω-6, pro-inflammatory), whereas α-linolenic acid is converted to eicosapentaenoic acid (EPA, 20:5ω-3, anti-inflammatory) and docosahexaenoic acid (DHA, 22:6ω-3, anti-inflammatory) via the same pathway, leading to enzyme competition between the two classes of PUFA. 8 While the phospholipid composition in human immune cells can vary, in an approximate 70:20:10 mixture of T lymphocytes:B lymphocytes:monocytes, 15%-25% of the phospholipids were ARA while 0.1%-0.8% and 2%-4% were EPA and DHA, respectively. 9,10 By supplementing the diet with ω-3 FAs, the proportion of EPA and DHA in immune cells can be elevated at the expense of ARA [8] [9] [10] and leads to the production of less inflammatory eicosanoids ( Figure 2 and Table 1 ).

Eicosanoids are important regulators of inflammation and comprise prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs), and lipoxins (LXs). [11] [12] [13] These molecules are converted from PUFAs by cyclooxygenase (COX), lipoxygenase (LOX), and Cytochrome P450 enzymes. Eicosanoids released by ARA metabolism are mostly proinflammatory and are the target of nonsteroidal anti-inflammatory drugs used in suppressing inflammation. 7 Prior to the synthesis of eicosanoids, ARA is released from the sn-2 position of the membrane phospholipids by the action of phospholipase A 2 enzymes, activated by inflammatory stimuli. 14 ARA metabolism results in two-series (two double bonds) PGs and TXs as well as four-series (four double bonds) LTs and LXs. COX-2 is induced in cells by inflammatory stimuli, resulting in a large increase in PG production. PGE 2 , other two-series PGs, and the four-series LTs are among the best-known activators of inflammation 11, 12, 15 and usually act through GPCRs. 16 ω-3 PUFAs such as EPAs are similarly metabolized by COX, LOX, and Cytochrome P450. However, EPA metabolism yields three-series (three double F I G U R E 1 Overview of discussed immunomodulatory lipids. Immunomodulatory lipids either activate or suppress immune activation. Certain eicosanoids (metabolic products of ω-3 and ω-6 PUFA: prostaglandins, thromboxanes, and leukotrienes) and lipid adjuvants (virosomes, MPLA, and MF59) are pro-inflammatory. Other eicosanoids such as lipoxins, the specialized pro-resolving lipid mediators (metabolic products of ω-3 PUFA; resolvins, protectins, and maresins), and SCFAs (acetate, propionate, and butyrate) are anti-inflammatory. Natural lipids and their derivatives are shaded in blue, synthetic lipids are shaded in violet. MPLA, monophosphoryl lipid A; PUFA, polyunsaturated fatty acid; SCFAs, short-chain fatty acids bonds) PGs and TXs, and five-series (five double bonds) LTs. 14 By incorporating more ω-3 PUFAs into the available pool of PUFAs, the amount of pro-inflammatory eicosanoids is reduced by competition between ARA and the ω-3 PUFAs. 17 However, the metabolism of the ω-3 PUFAs is not regulated solely by supply and demand. EPA itself can negatively regulate COX-2 gene expression and inhibit ARA metabolism. 18 The eicosanoids produced from metabolism of ω-3

PUFAs such as EPAs are structurally distinct from those produced by ARA 14 and are less biologically potent, 19,20 potentially due to a reduced receptor affinity. 21 An important class of eicosanoids produced by the metabolism of both ω-3 and ω-6 PUFAs (overwhelmingly ω-3 PUFA) are the specialized pro-resolving lipid mediators (SPMs). This family of mediators include resolvins produced by EPA (E-series) and DHA (D-series) as well as protectins and maresins produced by DHA. Two series of resolvins and protectins have been identified. One series includes those derived from EPA and DHA via lipoxygenase metabolism, referred to as the Sresolvins, S-protectins, and S-maresins. The second series includes those derived from aspirin-triggered cyclooxygenase (COX-2) or Cytochrome P450 metabolism of EPA and DHA. These lipid mediators are R-resolvins and R-protectins also known as aspirin-triggered resolvins/ protectins. This specialized pathway is transcellular, in which different cells start and end the metabolic pathway. [22] [23] [24] For example, lipoxin A 4 is a SPM that determines the extent of granulocyte accumulation and activation during inflammation. Lipoxin A 4 formation is achieved by the transcellular biosynthesis of two sequential oxygenation reactions of ARA catalyzed by LOX in interacting cell types. One of these cells is typically a neutrophil, eosinophil, or macrophage and the other is an endothelial, epithelial, parenchymal cell, or platelet. 25 Cell culture and animal studies have shown these metabolites to be anti-inflammatory and inflammation resolving. For example, resolvin E1, resolvin D1, and protectin D1 all inhibited transendothelial migration of neutrophils, preventing the infiltration of neutrophils into sites of inflammation; resolvin D1 inhibited interleukin-1β (IL-1β) production; and protectin D1 inhibited tumor necrosis factor (TNF) and IL-1β production. [22] [23] [24] SPMs have been shown to influence the adaptive immune system as well. For example, D-series resolvins and maresin 1 reduced cytokine production by activated CD8 + T cells and CD4 + T helper (Th)1 and Th17 cells while F I G U R E 2 Overview of the key immunomodulatory effects of PUFAs. Free ω-3 fatty acids (EPA and DHA) compete with free ω-6 fatty acids (e.g. ARA) for cell membrane insertion and metabolism by COX, LOX, and Cytochrome P450 enzymes. Metabolism of ω-3 and ω-6 PUFA results in inflammatory or anti-inflammatory eicosanoids respectively while metabolism of primarily ω-3 PUFA can result in SPMs (resolvins, protectins, and maresins). ω-3 PUFA in the cell membrane can disrupt lipid rafts housing receptors such as TLR-4 and prevent inflammatory stimulation. ω-3 PUFA, SPMs, and eicosanoids of ω-3 PUFA can bind to and regulate PPAR-γ, which subsequently binds and interferes with the translocation of NFκβ to the nucleus. ω-3 PUFA can also act in an anti-inflammatory manner by agonizing GPR120, which causes signal interference with the NFκβ pathway. The figure was created with BioRender.com. ARA, arachidonic acid; COX, cyclooxygenase; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; LOX, lipoxygenase; NFκβ, nuclear factor κβ; PPAR-γ, peroxisome proliferator activated receptor gamma; PUFAs, polyunsaturated fatty acids; SPMs, short-chain fatty acids simultaneously preventing naïve CD4 + T-cell differentiation into Th1 and Th17. 26 SPMs also influence the intracellular production and extracellular release of interferon-γ (IFN-γ) from Th1 cells and IL-17 from Th17 cells. Splenic T cells from mice deficient for elongase 2, the key enzyme involved in the synthesis of DHA from EPA, produced higher amounts of IFN-γ and IL-17 compared to cells from wild-type control mice. 26 generation and function of FoxP3 + regulatory T cells (T reg ) in the presence of D-series resolvins and maresin 1 is enhanced. 26 T reg cultured with SPMs showed significantly enhanced FoxP3 expression, as well as increased expression of the immune checkpoint molecule CTLA-4 and higher production of the anti-inflammatory IL-10 cytokine. Diet enrichment of EPA in mice, 27 as well as humans, 28 increased the concentration of resolvins in the blood and serum. Furthermore, resolvins reduced inflammation in a rat arthritis model. 29 Frequent administration of the precursor of aspirin-triggered resolvin D1 prevented joint stiffness but did not modify paw and joint edema in rats. 29 Transgenic mice expressing fat-1, a gene encoding an enzyme that converts ω-6 to ω-3

PUFA, showed significant improvement in a collagen induced arthritis mouse model. 30 Clinical arthritis score, inflammatory cell infiltration, and inflammatory cytokine expression in the spleen and ankle were attenuated while T reg expansion and differentiation was enhanced in fat-1 mice compared to wild-type mice. 

A third proposed mechanism of PUFA regulation of NFκβ involves GPR120, a GPCR expressed on macrophages. 50 ω-3 PUFAs, agonists of GPR120, inhibited the macrophage response to endotoxin, an effect which involved maintenance of cytosolic inhibitor of nuclear factor kappa B (Iκβ) and a decrease in production of TNF and IL-6, suggesting that GPR120 is involved in anti-inflammatory signaling. 50

Iκβ binds to NF-κβ to form an inactive complex where the common pathway for NF-κβ activation is based on phosphorylation-induced, proteasome-mediated degradation of Iκβ. 51 Therefore, a maintenance of cytosolic Iκβ regulates activation of NF-κβ. The effects produced by the synthetic agonist were similar to those produced by DHA and EPA. 50 It was observed that both EPA and DHA, but not ARA enhanced GPR120-mediated gene activation. 50 Moreover, the ability of DHA to inhibit the responsiveness of macrophages to endotoxin was eliminated in GPR120 knockdown cells. These data support that the inhibitory effect of DHA on NFκβ might occur via GPR120 due to signal interference with the pathway that activates NFκβ.

SCFAs are carboxylic acids and are one to six carbon atoms in length.

Acetate (two carbons), propionate (three carbons), and butyrate (four . AAI was not mitigated in GPR41 À/À mice treated with propionate after house dust mite exposure, but the same treatment ameliorated AAI in wild-type and GPR43 À/À mice. 68 Neutrophilassociated GPR43 has been shown to have a role in the recruitment of polymorphonuclear leukocyte to the site of inflammation, likely in a protein kinase p38α-dependent manner. 69 GPR43 activation has also been shown to induce chemotaxis of neutrophils in vitro. 70 inflammasome and enhances the production of IL-18, a critical component for maintaining epithelial integrity and intestinal homeostasis. 71 As with ω-3 PUFA derivatives, SCFA suppress cell adhesion molecules expressed by activated monocytes, neutrophils, and

Overview of the mechanisms of SCFA-mediated immune modulation. SCFAs are produced by anaerobic metabolism of dietary fiber in the gut by bacteria. These two-carbon (acetate), three-carbon (propionate), and four-carbon (butyrate) metabolic products influence the immune system by two modes of action, GPCR activation and HDAC inhibition. SCFAs modulate the innate immune system by activating GPR41, GPR43, and GPR109a, which are expressed on cells such as monocytes, neutrophils, and macrophages. SCFAs modulate the adaptive immune system by inhibiting HDAC, leading to modulation of the mTOR pathway, subsequently modifying the ratio of effector to regulatory T cells. The figure was created with BioRender.com. GPCR, G-protein-coupled cell membrane receptor; HDAC, histone deacetylase; mTOR, mammalian target of rapamycin; SCFA, short-chain fatty acids endothelial cells, mitigating the infiltration of inflammatory immune cells. [72] [73] [74] Acetate inhibits LPS-stimulated TNF production by peripheral blood mononuclear cells in both mice and humans via GPR43. 75 GPR43 activation has been demonstrated to induce the differentiation and enhance the function of FoxP3 + T regs through epigenetic modulation. 76 3.2 | SCFA-mediated adaptive immune cell modulation by histone deacetylase inhibition which can be acetylated at lysine 516 by HDAC inhibitors (e.g., SCFAs) and coactivator p300. 59 S6K phosphorylates ribosomal protein 6 (rS6), which is an important target in the mammalian target of rapamycin (mTOR) pathway and is a key metabolic pathway in T cells. In general, mTOR activity promotes effector T cells at high levels and promotes T reg at low levels. Increased phosphorylation of rS6 was observed under acetate and propionate supplementation. 77 Therefore, SCFAs can increase mTOR activity and support the generation of both effector and T reg .

It has also been demonstrated that SCFA promote the function of T regs . 76 SCFAs increase the activity of FoxP3 + T cells and IL-10 production via HDAC inhibition, which regulates gene expression of the (TCR)β À/À Tcrδ À/À mice, and NOD-scid IL2Rgamma null (NSG) mice grafted with purified B cells. 83 These effects were extended to autoantibody responses in lupus-prone MRL/Fas lpr/lpr and NZB/W F1 mice, 83 supporting a potential role of SCFA in systemic lupus erythematosus therapy.

SCFAs have been demonstrated to be immune modulating in a range of autoimmune diseases, particularly those that affect the gut. In active IBDs including Crohn's disease (CD), and ulcerative colitis (UC), SCFAproducing bacteria (particularly those of phylum Firmicutes) are reduced, leading to dysbiosis. In particular, a decrease in Firmicutes prausnitzii, a butyrate producing bacteria from the Clostridium cluster IV, is an indicator of IBD. 84, 85 Dysbiosis results in a decreased amount of SCFAs in the fecal matter of patients with IBD. 77 One study found that acetate and propionate, but not butyrate, are reduced in UC patients 86 while a separate study found both butyrate and propionate to be reduced in IBD patients. 87 The apparent differences might be attributed to dietary differences and the method of analysis. 86 In a rat sepsis model, butyrate prevented liver, kidney, and lung damage, thereby improving the survival rates. 90 The increase in survival rate was shown to be caused by downregulation of high-mobility group box protein 1 (HMGB1) by butyrate supplementation, which is a pro-inflammatory cytokine that activates multiple membrane receptors, including receptors for advanced glycation end products 91 SCFAs have the potential to exacerbate inflammation. For example, it has been documented that chronic elevation of SCFA higher than physiological levels can cause T-cell-induced inflammatory responses in the renal system. 80 In addition, in mouse models of colonic inflammation, the therapeutic effect of SCFA has been inconsistent and may be context dependent. For example, SCFA enemas did not prevent or reduce intestinal damage in 2,4,6-trinitrobenzene sulfonic-acid (TNBS)induced colitis in rats 95 but reduced colonic mucosal damage and serum inflammatory cytokines (IL-6, TNF, and IL-1β) in dextran sodium sulfate (DSS)-treated mice. 96 In contrast, butyrate did not prevent DSSinduced intestinal damage in mice exposed to antibiotics. 97 preparations. Therefore, subunit vaccine development often relies on adjuvants, which are molecular components that can safely boost the immunogenicity of the vaccine. Since its initial use in the 1920s, insoluble aluminum salts (alum) remained the only adjuvant in licensed vaccines for several decades. 99 As the overall effectiveness of an immunization regimen can be improved by adjuvanting the vaccine formulation, the development of new adjuvants is an important focus in vaccines formulations. 100 In particular, an evolving understanding of the relationship between lipids and antigen presenting cells has made it possible to design safe lipid adjuvants with strong and robust immune stimulating effects (Figure 4 ).

It is known that free cationic lipids, such as those with quaternary ammonium head groups, disrupt cell monolayers and can cause hemo- 115 Despite its low viral content, Inflexal ® imparts a robust immune response compared to conventional influenza vaccines. 116, 117 Virosomes are also being further explored for malaria and respiratory syncytial virus vaccines. 118 

MF59 is a safe and effective vaccine adjuvant, formulated as an oil-inwater nanoemulsion of squalene that produces approximately 160-nm-sized droplets, 125 showed that the cellular influx observed in CCR2 +/+ mice was significantly different than the influx found with CCR2 À/À mice, supporting the theory that cellular recruitment is the mode of action of MF59. 129 Another study showed that mice deficient in ICAM-1 showed significantly lower antibody titers against a Plasmodium falciparum vaccine than did wild type controls. 130 This ICAM-1 dependent immune response was found to be a specific mechanism for emulsion adjuvants such as MF59 but not for immune potentiator adjuvants such as MPLA. In vitro studies with MF59 found that rather than DCs being the target of this adjuvant, monocytes, macrophages, and granulocytes were targeted by MF59. 131 Accordingly, it was postulated that a key component of the mechanism of MF59 was chemokine-driven immune cell recruitment and chemokine-release that would create a positive feedback loop, strongly enhancing the numbers of immune cells at the injection site. These cells could then further participate in antigen uptake and transport to the draining lymph nodes. AS03 ® is another squalene, oil-in-water emulsion adjuvant that was approved for use as an emergency pandemic adjuvant for influenza by the European Medicines Agency. AS03 ® was more effective than alum in inducing a high antigen-specific antibody response and induced higher levels of cytokines and stimulated more monocyte and granulocyte recruitment to the draining lymph nodes than aluminum hydroxide. 132 

Lipids are important mediators of immune homeostasis and may be leveraged for treating a range of disorders. Their full potential as stand-alone immunomodulators or adjuvants is only now beginning to be realized. In this review, we focused on three classes of lipids-two The immunomodulatory effect of PUFA has been assessed solely based on diet supplementation. 17, 134, 135 Unlike SCFA, the immune modulating properties of PUFA are not due to the PUFA themselves, but rather from the eicosanoids derived from PUFA metabolism. [11] [12] [13] Therefore, an additional consideration is the metabolism of PUFA in target tissues. Reflecting this complexity, clinical trials using ω-3 PUFA have garnered mixed results. For example, dietary supplementation of ω-3 PUFA has been extensively studied in the context of cardiovascular disease. 136 (6) 

In vivo cyclooxygenase expression in synovial tissues of patients with rheumatoid arthritis and osteoarthritis and rats with adjuvant and streptococcal cell wall arthritis

The role of leukotrienes in asthma

Dietary polyunsaturated fatty acids improve histological and biochemical alterations in rats with experimental ulcerative colitis

Distribution of omega-6 and omega-3 polyunsaturated fatty acids in the whole rat body and 25 compartments

Short chain fatty acids in human large intestine, portal, hepatic and venous blood

Omega-3 fatty acids and inflammatory processes: From molecules to man

Polyunsaturated fatty acids, inflammation and immunity

The effects of short-and long-term supplementation with fish oil on the incorporation of n-3 polyunsaturated fatty acids into cells of the immune system in healthy volunteers

Encapsulated fish oil enriched in α-tocopherol alters plasma phospholipid and mononuclear cell fatty acid compositions but not mononuclear cell functions

Leukotrienes and Other Products of the 5-Lipoxygenase Pathway

Mixed messages: modulation of inflammation and immune responses by prostaglandins and thromboxanes

Regulation of immune responses by prostaglandin E 2

Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance

Cytochrome P450 pathways of arachidonic acid metabolism

A Consideration of Biomarkers to be Used for Evaluation of Inflammation in Human Nutritional Studies

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Nuclear factor-κB: Its role in health and disease

Differential effects of prostaglandin derived from ω-6 and ω-3 polyunsaturated fatty acids on COX-2 expression and IL-6 secretion

Human neutrophil chemotactic and degranulating activities of leukotriene B5 (LTB5) derived from eicosapentaenoic acid

Enzymes and receptors of prostaglandin pathways with arachidonic acid-derived versus eicosapentaenoic acid-derived substrates and products

Resolvins: A family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals

Resolving inflammation: Dual anti-inflammatory and pro-resolution lipid mediators

Specialized pro-resolving lipid mediators in the inflammatory response: An update

Transcellular regulation of eicosanoid biosynthesis

Proresolving lipid mediators resolvin D1, resolvin D2, and maresin 1 are critical in modulating T cell responses

Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells: Autacoids in antiand regulation of the mTOR-S6K pathway

The microbial metabolite butyrate induces expression of Th1-associated factors in cD4+ T cells

Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice

SCFAs train T cells in the gut to fight autoimmunity in the brain

Role of free fatty acid receptors in the regulation of energy metabolism

The orphan G proteincoupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids

Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells

Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation

Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43

Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis

Short-chain fatty acids stimulate the migration of neutrophils to inflammatory sites

SCFAs induce mouse neutrophil chemotaxis through the GPR43 receptor

Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome

Cholesteryl butyrate solid lipid nanoparticles inhibit adhesion of human neutrophils to endothelial cells

Butyrate inhibits leukocyte adhesion to endothelial cells via modulation of VCAM-1

Butyrate inhibits cytokine-induced VCAM-1 and ICAM-1 expression in cultured endothelial cells: The role of NF-κB and PPARα

G protein-coupled receptor 43 moderates gut inflammation through cytokine regulation from mononuclear cells

The microbial metabolites, short-chain fatty acids, regulate colonic T reg cell homeostasis. Science

Short chain fatty acids (SCFAs)mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases

Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation

Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells

Chronically elevated levels of short-chain fatty acids induce T cell-mediated ureteritis and hydronephrosis

Regulation of the effector function of CD8+ T cells by gut microbiota-derived metabolite butyrate

Microbiota-derived shortchain fatty acids promote the memory potential of antigen-activated CD8+ T cells

B cell-intrinsic epigenetic modulation of antibody responses by dietary fiber-derived shortchain fatty acids

Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease

Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases

A decrease of the butyrateproducing species roseburia hominis and faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis

The impact of the level of the intestinal short chain fatty acids in inflammatory bowel disease patients versus healthy subjects

Butyrate inhibits NF-κB activation in lamina propria macrophages of patients with ulcerative colitis

Butyrate inhibits inflammatory responses through NFκB inhibition: Implications for Crohn's disease

Sodium butyrate prevents lethality of severe sepsis in rats

RAGE as a receptor of HMGB1 (amphoterin): roles in health and disease

Increasing numbers of hepatic dendritic cells promote HMGB1-mediated ischemia-reperfusion injury

Sodium butyrate alleviates LPS-induced acute lung injury in mice via inhibiting HMGB1 release

Short-chain fatty acid propionate protects from hypertensive cardiovascular damage

Short-chain fatty acid enemas fail to decrease colonic hypersensitivity and inflammation in TNBS-induced colonic inflammation in rats

Microbial metabolite butyrate facilitates M2 macrophage polarization and function

The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition

Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients

Alum adjuvanticity: Unraveling a century old mystery

Emerging concepts in the science of vaccine adjuvants

The adjuvant activity of aliphatic nitrogenous bases

Liposomal cationic charge and antigen adsorption are important properties for the efficient deposition of antigen at the injection site and ability of the vaccine to induce a CMI response

Cationic lipids as onecomponent vaccine adjuvants: A promising alternative to alum

PEI-A potent, but not harmless, mucosal immuno-stimulator of mixed T-helper cell response and FasLmediated cell death in mice

A two-stage poly(ethylenimine)-mediated cytotoxicity: Implications for gene transfer/therapy

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Use of autoantigen-loaded phosphatidylserine-liposomes to arrest autoimmunity in type 1 diabetes

Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses

The virosome concept for influenza vaccines

Immunopotentiating reconstituted influenza virus virosome vaccine delivery system for immunization against hepatitis A

Epaxal ® : A virosomal vaccine to prevent hepatitis A infection

Eleven years of Inflexal ® V-a virosomal adjuvanted influenza vaccine

Rate, intensity, and duration of local reactions to a virosome-adjuvanted vs. an aluminium-adsorbed hepatitis A vaccine in UK travellers

Liposomal formulations in clinical use: An updated review

Immunogenicity of new virosome influenza vaccine in elderly people

Immunogenicity of trivalent subunit versus virosome-formulated influenza vaccines in geriatric patients

Vaccination with virosomally formulated recombinant CyRPA elicits protective antibodies against Plasmodium falciparum parasites in preclinical in vitro and in vivo models. npj Vacc

Development of a virosomal RSV vaccine containing 3D-PHAD ® adjuvant: formulation, composition, and long-term stability

Peptides as requirement for immunotherapy of the guinea-pig line-10 tumor with endotoxins

Purification and structural determination of nontoxic lipid A obtained from the lipopolysaccharide of Salmonella typhimurium

The vaccine adjuvant monophosphoryl lipid A as a TRIFbiased agonist of TLR4

TLR4-mediated proinflammatory dendritic cell differentiation in humans requires the combined action of MyD88 and TRIF

The role of MyD88-and TRIF-dependent signaling in monophosphoryl lipid A-induced expansion and recruitment of innate immunocytes

The development of selfemulsifying oil-in-water emulsion adjuvant and an evaluation of the impact of droplet size on performance

MF59 is a safe and potent vaccine adjuvant that enhances protection against influenza virus infection

Combination adjuvants for the induction of potent, long-lasting antibody and T-cell responses to influenza vaccine in mice

The mechanism of action of MF59 -An innately attractive adjuvant formulation. Vaccine

Immunization with the adjuvant MF59 induces macrophage trafficking and apoptosis

The requirement of CD80, CD86, and ICAM-1 on the ability of adjuvant formulations to potentiate antibody responses to a Plasmodium falciparum blood-stage vaccine

The adjuvants aluminum hydroxide and MF59 induce monocyte and granulocyte chemoattractants and enhance monocyte differentiation toward dendritic cells

Adjuvant system AS03 containing α-tocopherol modulates innate immune response and leads to improved adaptive immunity

Production rates and metabolism of short-chain fatty acids in the colon and whole body using stable isotopes

Dietary fish oil reduces intercellular adhesion molecule 1 and scavenger receptor expression on murine macrophages

Dietary fish oil diminishes lymphocyte adhesion to macrophage and endothelial cell monolayers

Marine omega-3 (N-3) fatty acids for cardiovascular health: An update for 2020

Cardiovascular effects of marine omega-3 fatty acids

Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia

Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: The STRENGTH Randomized Clinical Trial

Marine n-3 fatty acids and prevention of cardiovascular disease and cancer

Effects of n-3 fatty acid supplements in diabetes mellitus

Gut-microbiotatargeted diets modulate human immune status

Treatment of diversion colitis with short-chain-fatty acid irrigation

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Treatment of distal ulcerative colitis with short-chain fatty acid enemas. A placebocontrolled trial

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Treatment of diversion colitis by short-chain fatty acids-Prospective and double-blind study

Omega 3 fatty acids as a host modulator in chronic periodontitis patients: A randomised, double-blind, palcebo-controlled, clinical trial

MF59-adjuvanted influenza vaccine (FLUAD ® ) elicits higher immune responses than a non-adjuvanted influenza vaccine (Fluzone ® ): a randomized, multicenter

Safety and immunogenicity of influenza A(H5N1) vaccine stored up to twelve years in the National Pre-Pandemic Influenza Vaccine Stockpile (NPIVS)

Comparison of the safety and immunogenicity of an MF59 ® -adjuvanted with a nonadjuvanted seasonal influenza vaccine in elderly subjects

Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women

Hepatitis A vaccine for immunosuppressed patients with rheumatoid arthritis: A prospective, open-label, multi-centre study

Virosome-formulated Plasmodium falciparum AMA-1 & CSP derived peptides as malaria vaccine: Randomized phase 1b trial in semi-immune adults & children

Long-term antibody persistence in children after vaccination with the pediatric formulation of an aluminum-free virosomal hepatitis a vaccine

Omega-3 fatty acids reduce obesity-induced tumor progression independent of GPR120 in a mouse model of postmenopausal breast cancer

n-3 PUFAs reduce tumor load and improve survival in a NASH-tumor mouse model

Maternal intake of high n-6 polyunsaturated fatty acid diet during pregnancy causes transgenerational increase in mammary cancer risk in mice

Docosahexaenoic acid in the inhibition of tumor cell growth in preclinical models of ovarian cancer

Prostaglandin E3 attenuates macrophage-associated inflammation and prostate tumour growth by modulating polarization

Membrane therapy using DHA suppresses epidermal growth factor receptor signaling by disrupting nanocluster formation

Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer

Clostridium butyricum, a butyrateproducing probiotic, inhibits intestinal tumor development through modulating Wnt signaling and gut microbiota

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The authors are supported in part by the Arthritis National Research Foundation and the National Institutes of Health.

The authors declare no conflict of interest. 

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Nisarg J. Shah https://orcid.org/0000-0003-1727-5732