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Review ArticleReview Article
Open Access

Pharmacological Modulation of Immune Responses by Nutritional Components

Marthe T. van Daal, Gert Folkerts, Johan Garssen and Saskia Braber
Clive Page, ASSOCIATE EDITOR
Pharmacological Reviews October 2021, 73 (4) 1369-1403; DOI: https://doi.org/10.1124/pharmrev.120.000063
Marthe T. van Daal
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG, Utrecht, The Netherlands (M.T.v.D., G.F., J.G., S.B.); and Danone Nutricia Research, 3584 CT, Utrecht, The Netherlands (J.G.)
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Gert Folkerts
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG, Utrecht, The Netherlands (M.T.v.D., G.F., J.G., S.B.); and Danone Nutricia Research, 3584 CT, Utrecht, The Netherlands (J.G.)
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Johan Garssen
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG, Utrecht, The Netherlands (M.T.v.D., G.F., J.G., S.B.); and Danone Nutricia Research, 3584 CT, Utrecht, The Netherlands (J.G.)
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Saskia Braber
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG, Utrecht, The Netherlands (M.T.v.D., G.F., J.G., S.B.); and Danone Nutricia Research, 3584 CT, Utrecht, The Netherlands (J.G.)
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Clive Page
Roles: ASSOCIATE EDITOR
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  • Fig. 1
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    Fig. 1

    Effects of nutritional components via AHR on the immune system. After AHR activation by a nutritional component, chaperone proteins dissociate and form a heterodimer with an aryl hydrocarbon receptor nuclear translocator. Target genes are transcribed and lead to anti-inflammatory effects on the immune system. ARNT, aryl hydrocarbon receptor nuclear translocator; DRE, dioxin responsive element. Created with BioRender.com.

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    Fig. 2

    Effects of nutritional components via RXR binding partners on the immune system. After nutritional component binding to the RXR binding partner, a corepressor complex is replaced by a coactivator complex leading to gene transcription. In this figure, the immunologic effects are shown for each binding partner, namely RAR (A), VDR (B), LXR (C), and PPAR (D). Aside from RXR as a binding partner, LXR (C) can be SUMOylated where corepressor complex can bind, inhibiting transcription. IL, interleukin; iNOS, inducible NOS; LXRE, LXR responsive element; PPRE, PPAR responsive element; RARE, retinoic acid responsive element; VDRE, vitamin D responsive element. Created with BioRender.com.

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    Fig. 3

    Effects of nutritional components via GPR on the immune system. Binding of a nutritional component to one of the GPRs results in dissociation of the Gβ and Gγ from the Gα subunit. Depending on the Gα subtype, signal transduction cascade is activated, leading to immunologic changes. GPR41 (A), GPR 43 (B), GPR109A (C), and GPR120 (D) are shown in this figure. ROS, reactive oxygen species. Created with BioRender.com.

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    Fig. 4

    Effects of nutritional components via TLR on the immune system. Dependent on the type of nutrition, TLR can have a proinflammatory or anti-inflammatory effect. Anti-inflammatory effects of TLR4 (A) or TLR2 (C) are mediated through TRIF or MyD88-dependent signal transduction cascade. Other nutritional components binding to TLR4 (B) or TLR2 (D) lead to anti-inflammatory responses. GRO, human growth-related oncogene; MIP, macrophage inflammatory protein; TRIF, TIR-domain-containing adapter-inducing interferon-β. Created with BioRender.com.

Tables

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    TABLE 1

    Literature overview nutritional components and their effect on the immune system via AHR

    ReceptorNutritional ActivatorConcentration and Mode of AdministrationType of StudyModelStimulant/Disease ModelEffectReference
    AHRI3C50 µMEx vivoBMDC from AHR+/+, AHR−/− mice and CD4+ T cells from OTII FoxP3egfp C57BL/6 miceLPSReversion of LPS-induced DC surface marker CD11c and decrease in LPS-induced IL-12 release. Increased frequency of Foxp3+ Treg (BMDC-naïve T-cell coculture)(Benson and Shepherd, 2011)
    DIM15 µMIn vitroNaive murine CD4+CD62L+ Th cellsAnti-CD3/CD28 monoclonal antibodies and shRNA against AHRInhibited expression of estrogen receptor α, GATA3 and IL-4, IL-5, IL-13. Foxp3 upregulation and RORγτ downregulation(Huang et al., 2013)
    I3CDiet containing 1000 ppmIn vivoAHR+/+, AHR+/− and AHR−/− C57BL/6j miceClostridium difficileIncreased survival after Clostridium difficile infection, increased Treg, group 3 innate lymphoid cells, and γδ T-cell populations in the gut(Julliard et al., 2017)
    I3C or DIM40 mg/kg i.p.In vivoC57BL/6 miceEAE model using AHR antagonist CD223191Reduced inflammatory cells, proinflammatory cytokines, Th17 population, and increased Treg population in lymph nodes and brain(Rouse et al., 2013)
    I3C or DIM100 µMIn vitroNaïve murine splenocytesConcanavalin A and AHR antagonist CD223191Suppressed Th17 differentiation and promoted Treg population(Rouse et al., 2013)
    I3C or DIM50 mg/kg oral gavageIn vivoAHR+/+ and AHR−/− C57BL/6 miceDelayed type hypersensitivity reaction using methylated bovine serum albumin and
    RAR-specific antagonist CH223191
    Suppression of delayed type hypersensitivity reaction, increase in Treg population, and decrease in Th17 population in draining lymph nodes and spleen(Singh et al., 2016)
    DIM20 mg/kg i.v.In vivoWT and Rag−/− Thy1.1+ and Thy1.2+ C57BL/6 miceEAE model using myelin oligodendrocyte glycoprotein and RAR-specific antagonist CH223191Reduction of proinflammatory cytokines, IL-17A, IFN-γ, TNF-α, and IL-1β and inhibition of Th1 and Th17 cells, while maintaining Foxp3 expression and Treg development in brain and spinal cord(Yang et al., 2020)
    • GATA3, GATA-binding protein 3; ROR, retinoic acid receptor-related orphan receptor; shRNA, short hairpin RNA.

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    TABLE 2

    Literature overview nutritional components and their effect on the immune system via RXR binding partners: RAR, VDR, LXR, and PPAR

    ReceptorNutritional ActivatorConcentration and Mode of AdministrationType of StudyModelStimulant/Disease ModelEffectReference
    RARAll-trans RA1000 nMIn vitroHuman immature DCs with the Langerhans cells phenotypeInflammatory cytokines, RARα antagonist BMS 614 and pan-RAR antagonist BMS493DC apoptosis in the absence of inflammatory stimuli and DC activation in the presence of inflammatory stimuli(Geissmann et al., 2003)
    All-trans RA10 nMIn vitro/ex vivoThymocytes from DO‐11.10 αβTCR‐Tg mice with a RAG‐2–deficient and B10.D2 background, and MHC class I and II double KO miceThymocytes stimulated with ionomycin and phorbol myristate acetate, naïve T cells stimulated with cytokines for Th1/Th2 development.
    RARα antagonists LE135 and LE540
    Th2 promotion and Th1 suppression dependent on the timing of stimulation(Iwata et al., 2003)
    All-trans RA10 nMIn vitroNaïve T cells and DCs from DO‐11.10 x RAG‐2−/− B10.D2, normal B10.D2, and BALB/c miceCultured with normal medium, under Th1 conditions or Th2 conditions. In T cell–DC cocultures, ovalbumin was used. RARα antagonist LE135Enhanced α4β7 integrin and CCR9 expression and suppressed expression of E-selectin ligands on T cells(Iwata et al., 2004)
    All-trans RA2 or 10 nMIn vitroHuman cord blood CD4+CD25− T cells, CD4+ T cells and CD11c+ DCs from BALB/c or AKR/J micePhytohemagglutinin, concanavalin A, IL-2, and RARα antagonist Ro41-5253Upregulation of FoxP3+ T cells(Kang et al., 2007)
    Vitamin A1 or 10 nMIn vitro/ex vivoCD4+ T cells from WT or CCR9−/− BALB/c mice with excessive, normal, or deficient vitamin A statusConcanavalin A, IL-2, and RAR agonists and antagonists. Some experiments included TGF-β1Induction of Itg-α4, important for T-cell
    migration
    (Kang et al., 2011)
    All-trans RA1 or 10 nMIn vitroDCs from BALB/cJ miceCharacterized fetal bovine serum, granulocyte-macrophage colony-stimulating factor and RARα antagonist AGN 194301Downregulation of CD11a and increase in MMP-9 production(Lackey et al., 2008)
    All-trans RA100 nMIn vitroCD4+ CD25− T cells from OT-II transgenic mice (C57BL/6 background)TGF-β, ovalbumin, and RARα antagonist LE135Inhibition of IL-6–driven induction of proinflammatory Th17 cells, stimulation of anti-inflammatory FoxP3+ Treg cell differentiation, and upregulation of α4β7 integrin(Mucida et al., 2007)
    RA2.5 nMIn vitro/ex vivoT cells from C57BL/6J WT and RARα-deficient miceIL-2, anti-CH3 with or without anti-CD28 antibodiesConversion of naïve T cells into FoxP3+ T regulatory cells(Nolting et al., 2009)
    RA10 nMIn vitro/ex vivoB cells isolated from dnRARαCD19Cre and dnRARα miceMice immunized with hapten acetyl-cholera toxinInduction of B cells to produce IgA antibodies(Pantazi et al., 2015)
    All-trans RA1000 nMIn vitroCoculture CD172a+ monocytes and lymphocytes from Swiss White Landrace pigsRARα antagonist Ro-41-5253Upregulation of β7 integrin and CCR9 in lymphocytes(Saurer et al., 2007)
    All-trans RA1 µMIn vitroT cells from BALB/c miceRARα antagonist Ro41-5253Increased expression of FoxP3+ cells even in Th17-favoring conditions(Schambach et al., 2007)
    RA5 or 25 nMIn vitroB cells from BALB/c miceTGF-β1 and RARα antagonist LE540Promotion of IgA isotype switching in B cells. RA in combination with TGF-β1 enhanced expression of CCR9 and α4β7 on B cells(Seo et al., 2013)
    RA25 nMIn vitroHuman tonsillar B cellsRARα antagonist LE540Promotion of IgA isotype switching in B cells(Seo et al., 2014)
    RA10 nMIn vitroCD4+ CD25− T cells from C57B/6 STAT6-deficient or WT miceIL-2 (Th0 condition), TGF-β + IL2 (iTreg condition), or TGF-β + IL-2 + IL-4 + IL-10 (Th3 condition). Identification of the RA-responsive element in the FoxP3 promoter regionReversion of STAT6 inhibition of the TGF-β1–mediated FoxP3 induction(Takaki et al., 2008)
    All-trans RA10 nMIn vitro/ex vivoDCs from BALB/c, C57BL/6, DO11.10/RAG−/−, BALB/c IL13−/−, vitamin A(−), and vitamin A(+) miceOVA peptide P323-339 and RARα antagonists LE135 and LE540Prevention of IL-13, IL-17A, TNF-α, and INF-γ production by Th cells(Yokota-Nakatsuma et al., 2014)
    VDRVitamin D325–100 nMIn vitroMouse primary peritoneal macrophagesLPS and siRNA-VDR transfectionNLRP3 activation and IL-1β release(Cao et al., 2020)
    1,25(OH)2D3100 nMIn vitroHuman myeloid leukemia cell lines, U937, NB4, HL60, ML1, human bone marrow–derived macrophages, human HaCat HT29, and U937 cells. Murine 32Dc13 cells and bone marrow cells from murine WT and VDR-deficient miceStimulation dependent on cell line/type usedRegulation of primate innate immunity and induced expression of the antimicrobial peptide cathelicidin(Gombart et al., 2005)
    1,25(OH)2D30.001–10 nMIn vitro/ex vivoBMDC from C57BL/6, WT and vitamin D null mutant mice—Inhibition of surface MHCII and costimulatory ligands B7-1, B7-2, and CD40(Griffin et al., 2000)
    1,25(OH)2D31–100 nMIn vitroPrimary human monocytes/macrophages/DCsIntracellular M. tuberculosis/M. tuberculosis–derived lipopeptide and VDR-antagonist ZK159222 or Cyp27B1 antagonistProtection against M. tuberculosis via cathelicidin activation. A link between TLRs and vitamin D–mediated innate immunity(Liu et al., 2006)
    1,25(OH)2D30.5–1.25 µMIn vitroHuman blood mononuclear cellsKetoconazole and VDR antagonist ZK191784 and ZK203278Accumulation of phospholipase Cγ1, T-cell growth, and proliferation(von Essen et al., 2010)
    1,25(OH)2D31 nMIn vitroHuman cell lines, SCC25, Calu-3, and U937, human adult and neonatal primary keratinocytes, human monocytes, and neutrophilsE. Coli or P. aeruginosaInduction of antimicrobial peptides cathelicidin and defensin β2(Wang et al., 2004)
    1,25(OH)2D310–100 nMIn vitro/ex vivoRAW264.7 cells and macrophages from COX2 WT and VDR KO C57BL/6/Sv129 miceLPSSuppression of Akt/NF-κB/COX-2(Wang et al., 2014)
    1,25(OH)2D350 ng (diet) or 100 nM (ex vivo)In vivo/ex vivoC57BL/6 WT and VDR KO mice and iNKT cells/splenocytes ex vivoαGalCerVDR KO resulted in abnormal function and growth of natural killer T cells. Increase in IL-4 and IFN-γ by natural killer T cells.(Yu and Cantorna, 2008)
    1,25(OH)2D325-50 ng/day/mouse (diet)In vivoCypKO and WT C57BL/6 miceαGalCer (intraperitoneal)1,25(OH)2D3 needed for normal NKT cell development(Yu and Cantorna, 2011)
    1,25(OH)2D32, 20, and 50 nMIn vitroHuman PBMC and THP-1 cellsLPS and
    siRNA-VDR transfection
    Transformation of LPS-induced M1 macrophages to M2 macrophages by upregulation of IL-10, arginase-1, VDR and IFN regulatory factor 4 and downregulation of TNF-α, IL-6, and INF regulatory factor 5 phosphorylation(Zhu et al., 2019)
    LXR22(R)-hydroxy-cholesterol and 25-hydro xycholesterol20 µl of 10 nM each earIn vivoCD1 and LXRα−/−, LXRβ−/−, LXRα/β−/− C57Bl/6 miceTPA-induced contact dermatitis or oxazolone-induced dermatitisDecrease in ear thickness, inflammation of dermis and epidermis, and proinflammatory cytokines TNF-α and IL-1α(Fowler et al., 2003)
    Cyanidin-3-O-β-glucoside10, 20, or 40 µMIn vitroMurine alveolar macrophagesLPS and
    siRNA-LXRα transfection
    Inhibited TNF-α, IL-1β, and IL-6 production by alveolar macrophages(Fu et al., 2014)
    22(R)-hydroxy cholesterol (22R), 24(S), 25 epoxy cholesterol, and 24-hydroxy cholesterol5 µMIn vitro/ex vivoRAW264.7 cells and macrophages from LXRαβ+/+ mice, LXRαβ−/− mice, or WT C57BL/6 miceLPS or poly I:C and
    siRNA-LXR transfection in RAW264.7 cells
    Repression of inducible NOS via SUMOylation-dependent transrepression pathway(Ghisletti et al., 2007)
    22(R)-hydroxy cholesterol2 µMIn vitro/ex vivoRAW264.7 cells and peritoneal macrophages from WT and LXR-null C57BL/6 miceLPS or Escherichia coliInhibition of inducible NOS(Joseph et al., 2003)
    22R-hydroxy cholesterol and 25-hydroxy cholesterolUnspecifiedIn vitroHuman DCs and
    HepG2 cells
    LPS and shRNA-LXRαInhibition of CCR7 expression(Villablanca et al., 2010)
    PPARDHA20 µMIn vitroRAW264.7 and Jurkat T cellsLPS or zymosan A and siRNA-PPARγIncreased expression of M2 markers, enhanced efferocytosis, and decrease in M1 markers(Chang et al., 2015)
    Chrysin1–100 µMIn vitroANA-1, RAW264.7, HEK-293 cells, and peritoneal macrophages from obese miceLPS, IL-4, and PPARγ-specific antagonist GW9662Decrease in M1 markers and increase in M2 markers(Feng et al., 2014)
    Apigenin7.5 µMIn vitroANA-1, RAW264.7, HEK-293 cells, and murine primary peritoneal macrophagesLPS or IL-4, PPARγ-specific antagonist GW9662, and shRNA-PPARγFavoring M2 polarization via inhibition of NF-κB(Feng et al., 2016)
    EPA0.1, 0.5, or 1.0 g/kg i.p.In vivo/ex vivoC57BL/10, BALB/c and CBA mice, murine splenocytes (ex vivo)Hearts from C57BL/10 or BALB/c mice transplanted into CBA mice and ex vivo PPARγ-specific antagonist bisphenol A diglycidyl etherReduced IL‐2, IFN‐γ, and IL‐12 and increased IL-10, number of CD4+CD25+ and CD4+CD25+Foxp3+ cells.(Iwami et al., 2009)
    EPA and DHA25, 50, or 100 µMIn vitroHuman PBMC, Th-cell assaysPMA,ionomycin and PPARγ-specific antagonist T0070907Reduction of IL-2, IL-4, and TNF-α in Th cells (DHA to a lesser extent than EPA)(Jaudszus et al., 2013)
    DHA50 µMIn vitroBone marrow–derived DCs from C56BL/6 miceLPS and PPARγ-specific antagonist GW9662Immature DC phenotype and inhibition of IL-12 via inhibition of NF- κBp65 nuclear translocation(Kong et al., 2010)
    EPA and DHA10 and 100 µMIn vitroHK-2 cellsLPS and PPARγ-specific antagonist bisphenol A diglycidyl etherDecrease in LPS-induced MCP-1 in an NF-κB–dependent manner(Li et al., 2005)
    PA and DHA0.5 mM PA and 50 µM DHAIn vitroRAW264.7 cellsLPS and PPARγ-specific antagonist GW9662Increased M2 markers dependent on the PPAR-γ and NF-κBp65 signal pathway(Luo et al., 2017)
    Oxidized EPA500 µl 3.3 mMIn vivoWT and PPARα−/− 129SV miceLPSInhibited rolling and adhesion in neutrophils and monocytes(Sethi et al., 2002)
    EPA100, 250, or 500 mg/kg/day i.p.In vivo/ex vivoBALB/c and C57BL/6 mice
    Mixed-lymphocyte reaction (splenocytes from donor BALB/c mice + lymph node cells from recipient mice)
    Hearts from BALB/c mice transplanted into C57BL/6 mice and ex vivo PPARγ specific antagonist GW9662Prolonged graft survival due to increased Treg/Th17 ratios in donor heart. Decrease in IL-6 and IL-17 and increase in TGF-β production in mixed-lymphocyte reaction(Ye et al., 2012)
    DHA50 µMIn vitroMonocytes (differentiated into DCs) and lymphocytes from human PBMCStimulation dependent on assay and PPARγ-specific antagonist GW9662Downregulation of costimulation and antigen presentation resulting in immature phenotype with increased chemotactic abilities, inhibition of IL-6, IL-10, and IL-12(Zapata-Gonzalez et al., 2008)
    • shRNA, short hairpin RNA; STAT, signal transducer and activator of transcription; HEK, Human Embryonic Kidney; THP-1, human monocytic leukemia.

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    TABLE 3

    Literature overview nutritional components and their effect on the immune system via G-protein–coupled receptors

    ReceptorNutritional ActivatorConcentration and Mode of AdministrationType of StudyModelStimulant/Disease ModelEffectReference
    GPR41High-fiber diet or low-fiber diet supplemented with acetylated, propionylated, or butyrylated high-amylose maize starchAd libitumIn vivoWT, GPR109A−/− and Igα−/− C57BL6/J miceDSS-induced colitisButyrate improved gut barrier function and increased colonic IgA. Upregulation of Aldh1a2 in BMDC and integrin αvβ8 in BMDC and DCs induced by butyrate mediated via GPR41 and GPR109A(Isobe et al., 2020)
    Acetate and propionate200 mM acetate in drinking water or
    10 nM acetate or 1 mM propionate (cell culture)
    In vivo/in vitroWT, GPR41−/−, and GPR43−/− C57BL/6 mice and murine intestinal cellsInduction of intestinal inflammation with ethanol and TNBS or infection with C. rodentium (mice).
    LPS or commensal bacterial extract and pertussis toxin, a GPR, such as GPR41 and GPR43, activation blocker (cells)
    GPR41−/− and GPR43−/− mice exhibited reduced inflammatory responses/slower immune response against infection.
    Increased expression of IL-6, CXCL-1, and CXCL-10
    (Kim et al., 2013)
    High-fiber dietNot specifiedIn vivoWT and GPR41−/− C57BL/6J miceHigh-fiber diet during pregnancy and lactationIncreased number of Treg cells in the thymus of offspring via enhancement of Aire expression(Nakajima et al., 2017a)
    Propionate or acetate.
    Low-fiber diet or high-fiber diet
    1 g/kg i.p. propionate or 200 mM acetate or propionate in drinking water.
    High-fiber diet containing 30% cellulose or 30% pectin
    In vivoWT, GPR41−/−, and GPR43−/− C57BL/6 miceHDM-induced allergic airway inflammationReduction of airway inflammation in a GPR41-dependent manner (propionate)(Trompette et al., 2014)
    GPR43Acetate, butyrate, and propionate10 nM acetate or propionate, 5 nM butyrateIn vitroMouse glomerular mesangial cells and VERSUS-40 MES 13GPR43 overexpression and siRNA-GPR43Inhibition of phosphorylated NF-κB and MCP-1 expression via GPR43–β-arrestin-2 pathway(Huang et al., 2020)
    Acetate and propionate200 mM acetate in drinking water or
    10 nM acetate or 1 mM propionate (cell culture)
    In vivo/in vitroWT, GPR41−/− and GPR43−/− C57BL/6 mice and murine intestinal cellsInduction of intestinal inflammation with ethanol and TNBS or infection with C. rodentium (mice).
    LPS or commensal bacterial extract and pertussis toxin, a GPR, such as GPR41 and GPR43, activation blocker (cells)
    GPR41−/− and GPR43−/− mice exhibited reduced inflammatory responses/slower immune response against infection.
    Increased expression of IL-6, CXCL-1, and CXCL-10
    (Kim et al., 2013)
    Acetate100, 200, or 300 mM in drinking waterIn vivoWT, GPR43−/− and GPR109A−/− C57BL/6 miceDSS-induced colitisImprovement of clinical scores, histologic scores, and colon length via activation of NLPR3 inflammasome dependent on GPR109A and GPR43 signaling(Macia et al., 2015)
    Acetate150 mM in drinking waterIn vivo/ex vivoWT, GPR43−/− C57BL/6 mice and germ-free mice,
    murine bone-marrow neutrophils ex vivo
    Inflammatory arthritis and OVA-induced acute allergic airway inflammation, DSS-induced colitisExacerbated colitis in germ-free mice is ameliorated by acetate. GPR43−/− showed more severe inflammation, whereas acetate reduced the inflammation (inflammatory arthritis).
    GPR43-dependent effects of acetate on neutrophil function
    (Maslowski et al., 2009)
    Acetate10 mMEx vivoMacrophages from WT, GPR43−/− and aP2-Gpr43TG C57BL/6 mice—No changes in M1/M2 polarization but higher TNF-α expression dependent on MAPK signaling in M2 phenotype(Nakajima et al., 2017b)
    Butyrate and propionate10 nMIn vivo/ex vivoNeutrophilic granulocytes (polymorphonuclear leukocytes) from WT and GPR43−/− C57BL/6 miceDSS-induced colitisGPR43−/− mice showed diminished intestinal migration of polymorphonuclear leukocytes but protection against inflammatory tissue destruction.
    GPR43 deficiency caused inhibited SCFA-induced chemotactic activity (p38 MAPK-dependent) and influenced l-selectin shedding
    (Sina et al., 2009)
    SCFAs or propionate150 mM SCFAs or propionate in drinking waterIn vivoWT, GPR43−/− C57BL/6 and germ-free mice—SCFAs restored Treg population in colon in germ-free mice and GPR43 mediated SCFA-induced effects on Treg cells, which is probably through HDAC inhibition(Smith et al., 2013)
    SCFAs0.1–100 mMEx vivoBone marrow–derived neutrophils from WT and GPR43−/− C57BL/6 × 129 mice—Induction of neutrophil chemotaxis via PI3Kγ, Rac2, and MAPKs(Vinolo et al., 2011)
    Acetate300 mM in drinking waterIn vivoWT and GPR43−/− C57BL/6 mice—Promotion of intestinal IgA via induction of Aldh1a1 in splenic dendritic cells(Wu et al., 2017)
    Butyrate100 mM in drinking waterIn vivo and ex vivoWT and GPR43−/− C57BL/6 mice, and ex vivo intestinal epithelial cellsAntibiotic treatment to eliminate gut microbiotaPromotion of antimicrobial peptide expression (RegIIIγ and β-defensins 1, 3, and 4) in intestinal epithelial cells via activation of mTOR and STAT3(Zhao et al., 2018)
    GPR109ANiacin0.1 mMIn vitroHuman monocytes and TCP-1LPS or Lysteria monocytogenes and siRNA-GPR109AReduction of TNF-α, IL-6, and MCP-1 via NF-κB inhibition(Digby et al., 2012)
    High-fiber diet or low-fiber diet supplemented with acetylated, propionylated, or butyrylated high-amylose maize starchAd libitumIn vivoWT, GPR109A−/− and Igα−/− C57BL6/J miceDSS-induced colitisButyrate improved gut barrier function and increased colonic IgA. Upregulation of Aldh1a2 in BMDC and integrin αvβ8 in BMDC and DCs induced by butyrate mediated via GPR41 and GPR109A(Isobe et al., 2020)
    Niacin100 µMIn vitroHuman mature blood neutrophilsPertussis toxin, a GPR activation blockerAcceleration of apoptosis in mature neutrophils due to less decreased cAMP leading to reduced Bad phosphorylation(Kostylina et al., 2008)
    Acetate100, 200, or 300 mM in drinking waterIn vivoWT, GPR43−/− and GPR109A−/− C57BL/6 miceDSS-induced colitisImprovement of clinical scores, histologic scores, and colon length via activation of NLPR3 inflammasome dependent on GPR109A and GPR43 signaling(Macia et al., 2015)
    β-Hydroxybutyrate100 mg/kg (administration route unknown) ketogenic dietIn vivoWT and GPR109A−/− C57BL/6 miceLeft middle cerebral artery occlusionReduction of consequences of ischemic stroke due to activation of anti-inflammatory microglia cells(Rahman et al., 2014)
    Butyrate and niacin25 mM in drinking waterIn vivo/ex vivoWT, IL18−/−, Apc-/+ and GPR109A+/− Apc−/− C57BL/6 mice, murine macrophages, and DCsDSS-induced colitis and azoxymethane-induced colon cancerGPR109A+/− mice showed enhanced risk for colon cancer and colitis. Induction of IL-10 and Aldh1a1, reduction of IL-17 in murine macrophages and DCs leading to an increase in Treg cells (by butyrate and niacin), GPR109A-dependent(Singh et al., 2014)
    Acetate, propionate, and butyrate200 mM acetate, 100 mM propionate, or 100 mM butyrate in drinking waterIn vivoWT and GPR109A−/− C57BL/6 miceIntragastric administration of peanut extractEnhancement of CD103+ DCs with increased expression of Aldh1a2 and increase in Treg populations(Tan et al., 2016)
    GPR120DHA30 mg/kg i.p. for in vivo and 10 µM ex vivoIn vivo and ex vivoWT and GPR120 KO Balb/c miceNaphthalene-induced airway injuryAccelerated resolving of airway injury by proliferation and migration of club cells(Lee et al., 2017)
    DHA100 µMIn vitroRAW-264.7 cellsLPS and siRNA-GPR120Suppression of NF-κB resulting in an anti-inflammatory response(Liu et al., 2014)
    EPA10, 20, or 30 mg/kg oral
    20 µM (in vitro)
    In vivo/in vitroNlpr3−/− and double-KO Gpr40−/− Gpr120−/− C57BL/6 mice
    BV2 microglia cells
    Right middle cerebral artery occlusion (in vivo).
    Oxygen-glucose deprivation, shRNA-GPR120, and shRNA-GPR40 (in vitro)
    Reduction of ischemic brain injury by upregulation of IL-1β and suppression of inflammasome NLRP3 (in vivo)
    Blocking of IL-1β maturation, IL-18 secretion, and caspase-1 cleavage (in vitro), both mediated via GPR40 and GPR120
    (Mo et al., 2020)
    High-fat diet and high-fat diet enriched with Ω-3 PUFAs DHA (in vitro)Ω-3 PUFAs containing 16% EPA and 9%, DHA
    100 µM DHA (in vitro)
    In vivo/in vitroWT and GPR120 KO C57BL/6J mice
    RAW-264.7 cells
    High-fat diet
    LPS and siRNA-GPR120
    Anti-inflammatory effects in high-fat diet–fed mice in adipose tissue. Increase in macrophage chemotaxis, M2 phenotype and decrease in M1in adipose tissue Downregulation of TNF-α, IL-6, and MCP-1 via GPR120/β -arrestin-2(Oh et al., 2010)
    DHA50 and 100 µMIn vitroHuman THP-1 cells and PBMCLPS and siRNA-GPR120Decreased NLRP3, AIM2, and NAIP/NLCR4 inflammasome activation(Williams-Bey et al., 2014)
    DHA, EPA, and α-linolenic acid20 µMIn vitroHuman THP-1 cellsshRNA-GPR120 and shRNA-GPR40Inhibition of IL-1β and caspase 1 activity via NLRP3 inflammasome mediated via both GPR120 and GPR40(Yan et al., 2013)
    GPR40Palmitic acid100 µMIn vitroMouse primary hepatocytes and RAW264.7 cellsLPS and GPR40-specific antagonist GW1100Synergistic work of LPS and palmitic leading to increased inflammation (increase in MCP-1, CD86, CSF-3, IL-1α, IL-1β, IL-6, and COX-2) in hepatocytes dependent on both GPR40 and CD36(Li et al., 2018)
    Oleic and linoleic acid200 µM oleic acid or 100 µM linoleic acidIn vitroHuman neutrophilsGPR40-specific antagonist GW1100Increase in CXCL-8, COX-2, and MMP-9 dependent on the MEK1/2-ERK1/2 pathway.(Mena et al., 2016)
    10-Hydroxy-cis-12-octadecenoic acid50 µMIn vitroCaco-2 and HEK293IFN-γ and TNF-α, GPR40-specific antagonist GW1100Improved barrier function by upregulation of ZO-1, ZO-2, and claudin-3 after INF-γ– and TNF-α–induced epithelial damage via MEK-ERK pathway(Miyamoto et al., 2015)
    EPA10, 20 or 30 mg/kg oral
    20 µM (in vitro)
    In vivo/in vitroNlpr3−/− and double-KO Gpr40−/−; Gpr120−/− C57BL/6 mice
    BV2 microglia cells
    Right middle cerebral artery occlusion (in vivo).
    Oxygen-glucose deprivation, shRNA-GPR120, and shRNA-GPR40 (in vitro)
    Reduction of ischemic brain injury by upregulation of IL-1β and suppression of inflammasome NLRP3 (in vivo)
    Blocking of IL-1β maturation, IL-18 secretion, and caspase-1 cleavage (in vitro), both mediated via GPR40 and GPR120
    (Mo et al., 2020)
    DHA, EPA, and α-linolenic acid20 µMIn vitroHuman THP-1 cellsshRNA-GPR120 and shRNA-GPR40Inhibition of IL-1β and caspase 1 activity via NLRP3 inflammasome, mediated via both GPR120 and GPR40(Yan et al., 2013)
    GPR81
    Lactate150 µM at 30 µl/g i.p.
    15 mM (in vitro)
    In vivo/in vitroC57BL/6N mice primary mouse macrophages, human monocytes, RAW 246.7 and Kupffer cells.Acute hepatitis (administration of LPS and d-galactosamine), acute pancreatitis (administration of LPS and caerulin). siRNA-GPR81 and siRNA-ARRB2In vivo protection against immune hepatitis and acute pancreatitis, GPR81-dependent.
    Suppression of LPS-induced pro-IL-1β, NLRP3, caspase 1, and pro-IL-18 via inhibition of NF-κB mediated via GPR81/ARRB2 (in vitro).
    (Hoque et al., 2014)
    Lactate10 mMIn vivo/ex vivoPrimary myometrial smooth muscle cells and uterine explants from timed-pregnant CD-1 mice, GPR81−/−, and GPR81 knocked-down miceIntraperitoneal injection LPS, IL-1β ex vivoAnti-inflammatory effects of lactate, including decreased mRNA expression of IL-1β, IL-6, MCP-1, and PGHS-2, via receptor GPR81 in the uterus during labor.(Madaan et al., 2017)
    T2RFlavones (apigenin, chrysin, and wogonin)10 µMIn vitroA549 and 16HBE cells, and primary sinonasal epithelial cell ciliaStimulation with phorbol 12-myristate 13-acetate, inducible NOS, or TNF-α, global PKC inhibitor Gö6983Reduction inflammation via downregulation of IL-18, granulate colony-stimulating factor, and granulocyte macrophage colony-stimulating factor(Hariri et al., 2017)
    Quinine56 µMIn vitroHuman sinonasal epithelial cells from healthy individuals and patients with chronic rhinosinusitis—Stimulation of the airway innate immune defense observed by an increase in nitric oxide and acceleration of ciliary beating related to T2R activation(Workman et al., 2018)
    • HEK, Human Embryonic Kidney; MAPK, Mitogen-Activated Protein Kinase; mTOR, mammalian target of rapamycin; shRNA, short hairpin RNA; STAT, signal transducer and activator of transcription; THP-1, human monocytic leukemia.

    • View popup
    TABLE 4

    Literature overview nutritional components and their effect on the immune system via TLRs

    ReceptorNutritional ActivatorConcentration and Mode of AdministrationType of StudyModelStimulant/Disease ModelEffectReference
    TLR2Normal or Western-like rodent dietAd libitumIn vivoWT and TLR2/4 double-KO C57BL6Crossfostering and TLR4 specific inhibitor TAK-242Maternal Western diet caused neonatal toxicity and inflammation, possibly related to long-chain fatty acids and SFAs in mother milk. TLR2/4 deletion rescues the neonatal toxicity(Du et al., 2012)
    Free fatty acids500 µMIn vitro/ex vivoRAW264.7 cells and BMDC from WT and TLR2/4 double-KO C57BL/6 miceRAW264.7 cells were treated with siRNA-TLR2/4Increase in proinflammatory cytokines(Nguyen et al., 2007)
    β2→1-fructan1 or 100 µg/mlIn vitroHuman PBMC, THP-1 cells, and TLR2 reporter cell lines—Elevated IL-10/IL-12 protein levels(Vogt et al., 2013)
    β2→1-fructan100 mg/lIn vitroT84 cellsPhorbol 12-myrestare 13-acetate and TLR2 blocking antibodyImprovement of intestinal epithelial barrier function(Vogt et al., 2014)
    TLR4FOS, inulin, GOS, and goat milk oligosaccharides0.005 –5 g/lIn vitro/ex vivoHuman peripheral blood monocytes, monocytes and lymphocytes from Wistar rats, and splenocytes from WT and TLR4−/− C57BL/6J miceLPS, concanavalin A, and MAPK inhibitorsNDOs generally evoked cytokine release by splenocytes and monocytes, possibly via activation of TLR4 and engagement of NF-ĸB and MAPK pathways NF-ĸB(Capitán-Cañadas et al., 2014)
    Normal or Western-like rodent dietAd libitumIn vivoWT and TLR2/4 double-KO C57BL6Crossfostering and TLR4-specific inhibitor TAK-242Maternal Western diet caused neonatal toxicity and inflammation, possibly related to long-chain fatty acids and SFAs in mother milk. TLR2/4 deletion rescues the neonatal toxicity(Du et al., 2012)
    Sodium palmitate and laurate100–500 µMIn vitroRAW 264.7 cells, immortalized MyD88−/− macrophages, and HEK293T cellsBovine serum albumin and polymyxin B and TLR4-specific inhibitor TAK-242Induction of COX-2 and TNF-α(Huang et al., 2012)
    Sialyl(α2,3)lactose25 mM in diet or 3 mg oral gavageIn vivoSt3gal4−/−, IL10−/−, St3gal4−/−;IL10−/− and TLR4−/− C57BL/J6 miceCrossfostering
    Spontaneous chronic intestinal inflammation
    Early onset and exacerbation of colitis symptoms, increased proinflammatory cytokines, proinflammatory monocytes, Th1 and Th17 cells(Kurakevich et al., 2013)
    Lauric acid50, 75, or 100 µMIn vitroRAW264.7 and 293T cells transfected with TLR4 and MD2Dominant-negative mutant of TLR4, MyD88, IRAK-1, TRAF6, or IĸBα.
    I3K inhibitor (LY294002) or a dominant-negative mutant of PI3K or AKT
    Activation of TLR4 and signaling pathways involving MyD88/IRAK/TRAF6 and PI3K/AKT(Lee et al., 2003)
    Short-chain GOS/long-chain FOS5 mg/mlIn vitroHuman monocyte–derived DCsLPS, Bifidobacterium breve, and TLR4-specific antagonistInduction of IL-10 secretion of (Bifidobacterium breve–stimulated) DCs(Lehmann et al., 2015)
    Palmitic acid50–300 µMIn vitroHuman monocyte–derived DCs and recombinant TLR4/MD2 HeLa cells—Upregulation of DC costimulatory factors CD86 and CD83 and expression of IL-1β by interacting with TLR4/MD-2(Nicholas et al., 2017)
    Free fatty acids500 µMIn vitro/ex vivoRAW264.7 cells and BMDC from WT and TLR2/4 double-KO C57BL/6 miceRAW264.7 cells were treated with siRNA-TLR2/4Increase in proinflammatory cytokines(Nguyen et al., 2007)
    Goat milk oligosaccharides, inulin, GOS, and FOS5 mg/mlIn vitro/ex vivoIEC18, HT29, Caco-2 and Caco‐2/TC7 cells and colon cells from WT and TLR4 KO C57BL/6J miceSpecific inhibitors of NF-κB and MAPK pathways, shRNA specific for MyD88 and TLR4 for gene knockdownNDOs stimulated cytokine production in intestinal epithelial cells (e.g., CXCL-1 and MCP-1)(Ortega-González et al., 2014)
    High-fat diet
    Palmitate and oleate
    Not specified (diet)
    200 or 400 µM (in vitro)
    In vivo/in vitroWT and TLR4−/− C57BL6/J mice, ob/ob and db/db mice. RAW264.7 cells and 293T 3T3-L1 adipocytes, isolated mouse adipocytes, adipose tissue, and peritoneal macrophages from TLR4−/− miceDiet-induced obesity siRNA-TLR4Diet-induced inflammation and insulin resistance, increased TLR4 expression in adipose tissue of obese/diabetic mice.
    Activation of TLR4 signaling, stimulation of cytokine expression (e.g., TNF-α, IL-6)
    (Shi et al., 2006)
    Palmitate100-200 µMIn vitro/ex vivoCoculture of 3T3-L1 and RAW264.7, Ba/F3,
    or TLR4 mutant peritoneal macrophages of C3H/HeJ or C3H/HeN mice
    TNF-α, LPSRole of TLR4/NF-κB pathway in SFA-induced inflammatory changes(Suganami et al., 2007)
    • HEK, Human Embryonic Kidney; IEC, intestinal epithelial cell line; MAPK = Mitogen-Activated Protein Kinase; shRNA, short hairpin RNA.

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Pharmacological Reviews: 73 (4)
Pharmacological Reviews
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1 Oct 2021
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Review ArticleReview Article

Nutrition, Pharmacological Receptors, and Immune Responses

Marthe T. van Daal, Gert Folkerts, Johan Garssen and Saskia Braber
Pharmacological Reviews October 1, 2021, 73 (4) 1369-1403; DOI: https://doi.org/10.1124/pharmrev.120.000063

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Review ArticleReview Article

Nutrition, Pharmacological Receptors, and Immune Responses

Marthe T. van Daal, Gert Folkerts, Johan Garssen and Saskia Braber
Pharmacological Reviews October 1, 2021, 73 (4) 1369-1403; DOI: https://doi.org/10.1124/pharmrev.120.000063
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