Pharmacological Modulation of Immune Responses by Nutritional Components

Marthe T. van Daal; Gert Folkerts; Johan Garssen; Saskia Braber

doi:10.1124/pharmrev.120.000063

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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 G_β and G_γ from the G_α subunit. Depending on the G_α 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.

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TABLE 1

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

Receptor	Nutritional Activator	Concentration and Mode of Administration	Type of Study	Model	Stimulant/Disease Model	Effect	Reference
AHR	I3C	50 µM	Ex vivo	BMDC from AHR^+/+, AHR^−/− mice and CD4+ T cells from OTII FoxP3^egfp C57BL/6 mice	LPS	Reversion 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)
	DIM	15 µM	In vitro	Naive murine CD4⁺CD62L⁺ Th cells	Anti-CD3/CD28 monoclonal antibodies and shRNA against AHR	Inhibited expression of estrogen receptor α, GATA3 and IL-4, IL-5, IL-13. Foxp3 upregulation and RORγτ downregulation	(Huang et al., 2013)
	I3C	Diet containing 1000 ppm	In vivo	AHR^+/+, AHR^+/− and AHR^−/− C57BL/6j mice	Clostridium difficile	Increased 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 DIM	40 mg/kg i.p.	In vivo	C57BL/6 mice	EAE model using AHR antagonist CD223191	Reduced inflammatory cells, proinflammatory cytokines, Th17 population, and increased Treg population in lymph nodes and brain	(Rouse et al., 2013)
	I3C or DIM	100 µM	In vitro	Naïve murine splenocytes	Concanavalin A and AHR antagonist CD223191	Suppressed Th17 differentiation and promoted Treg population	(Rouse et al., 2013)
	I3C or DIM	50 mg/kg oral gavage	In vivo	AHR^+/+ and AHR^−/− C57BL/6 mice	Delayed 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)
	DIM	20 mg/kg i.v.	In vivo	WT and Rag^−/− Thy1.1⁺ and Thy1.2⁺ C57BL/6 mice	EAE model using myelin oligodendrocyte glycoprotein and RAR-specific antagonist CH223191	Reduction 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

Receptor	Nutritional Activator	Concentration and Mode of Administration	Type of Study	Model	Stimulant/Disease Model	Effect	Reference
RAR	All-trans RA	1000 nM	In vitro	Human immature DCs with the Langerhans cells phenotype	Inflammatory cytokines, RARα antagonist BMS 614 and pan-RAR antagonist BMS493	DC apoptosis in the absence of inflammatory stimuli and DC activation in the presence of inflammatory stimuli	(Geissmann et al., 2003)
	All-trans RA	10 nM	In vitro/ex vivo	Thymocytes from DO‐11.10 αβTCR‐Tg mice with a RAG‐2–deficient and B10.D2 background, and MHC class I and II double KO mice	Thymocytes 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 RA	10 nM	In vitro	Naïve T cells and DCs from DO‐11.10 x RAG‐2^−/− B10.D2, normal B10.D2, and BALB/c mice	Cultured with normal medium, under Th1 conditions or Th2 conditions. In T cell–DC cocultures, ovalbumin was used. RARα antagonist LE135	Enhanced α4β7 integrin and CCR9 expression and suppressed expression of E-selectin ligands on T cells	(Iwata et al., 2004)
	All-trans RA	2 or 10 nM	In vitro	Human cord blood CD4⁺CD25⁻ T cells, CD4+ T cells and CD11c⁺ DCs from BALB/c or AKR/J mice	Phytohemagglutinin, concanavalin A, IL-2, and RARα antagonist Ro41-5253	Upregulation of FoxP3⁺ T cells	(Kang et al., 2007)
	Vitamin A	1 or 10 nM	In vitro/ex vivo	CD4⁺ T cells from WT or CCR9^−/− BALB/c mice with excessive, normal, or deficient vitamin A status	Concanavalin A, IL-2, and RAR agonists and antagonists. Some experiments included TGF-β1	Induction of Itg-α4, important for T-cell migration	(Kang et al., 2011)
	All-trans RA	1 or 10 nM	In vitro	DCs from BALB/cJ mice	Characterized fetal bovine serum, granulocyte-macrophage colony-stimulating factor and RARα antagonist AGN 194301	Downregulation of CD11a and increase in MMP-9 production	(Lackey et al., 2008)
	All-trans RA	100 nM	In vitro	CD4+ CD25⁻ T cells from OT-II transgenic mice (C57BL/6 background)	TGF-β, ovalbumin, and RARα antagonist LE135	Inhibition 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)
	RA	2.5 nM	In vitro/ex vivo	T cells from C57BL/6J WT and RARα-deficient mice	IL-2, anti-CH3 with or without anti-CD28 antibodies	Conversion of naïve T cells into FoxP3⁺ T regulatory cells	(Nolting et al., 2009)
	RA	10 nM	In vitro/ex vivo	B cells isolated from dnRARαCD19Cre and dnRARα mice	Mice immunized with hapten acetyl-cholera toxin	Induction of B cells to produce IgA antibodies	(Pantazi et al., 2015)
	All-trans RA	1000 nM	In vitro	Coculture CD172a⁺ monocytes and lymphocytes from Swiss White Landrace pigs	RARα antagonist Ro-41-5253	Upregulation of β7 integrin and CCR9 in lymphocytes	(Saurer et al., 2007)
	All-trans RA	1 µM	In vitro	T cells from BALB/c mice	RARα antagonist Ro41-5253	Increased expression of FoxP3⁺ cells even in Th17-favoring conditions	(Schambach et al., 2007)
	RA	5 or 25 nM	In vitro	B cells from BALB/c mice	TGF-β1 and RARα antagonist LE540	Promotion 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)
	RA	25 nM	In vitro	Human tonsillar B cells	RARα antagonist LE540	Promotion of IgA isotype switching in B cells	(Seo et al., 2014)
	RA	10 nM	In vitro	CD4⁺ CD25⁻ T cells from C57B/6 STAT6-deficient or WT mice	IL-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 region	Reversion of STAT6 inhibition of the TGF-β1–mediated FoxP3 induction	(Takaki et al., 2008)
	All-trans RA	10 nM	In vitro/ex vivo	DCs from BALB/c, C57BL/6, DO11.10/RAG^−/−, BALB/c IL13^−/−, vitamin A(−), and vitamin A(+) mice	OVA peptide P323-339 and RARα antagonists LE135 and LE540	Prevention of IL-13, IL-17A, TNF-α, and INF-γ production by Th cells	(Yokota-Nakatsuma et al., 2014)
VDR	Vitamin D3	25–100 nM	In vitro	Mouse primary peritoneal macrophages	LPS and siRNA-VDR transfection	NLRP3 activation and IL-1β release	(Cao et al., 2020)
	1,25(OH)₂D₃	100 nM	In vitro	Human 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 mice	Stimulation dependent on cell line/type used	Regulation of primate innate immunity and induced expression of the antimicrobial peptide cathelicidin	(Gombart et al., 2005)
	1,25(OH)₂D₃	0.001–10 nM	In vitro/ex vivo	BMDC 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)₂D₃	1–100 nM	In vitro	Primary human monocytes/macrophages/DCs	Intracellular M. tuberculosis/M. tuberculosis–derived lipopeptide and VDR-antagonist ZK159222 or Cyp27B1 antagonist	Protection against M. tuberculosis via cathelicidin activation. A link between TLRs and vitamin D–mediated innate immunity	(Liu et al., 2006)
	1,25(OH)₂D₃	0.5–1.25 µM	In vitro	Human blood mononuclear cells	Ketoconazole and VDR antagonist ZK191784 and ZK203278	Accumulation of phospholipase Cγ1, T-cell growth, and proliferation	(von Essen et al., 2010)
	1,25(OH)₂D₃	1 nM	In vitro	Human cell lines, SCC25, Calu-3, and U937, human adult and neonatal primary keratinocytes, human monocytes, and neutrophils	E. Coli or P. aeruginosa	Induction of antimicrobial peptides cathelicidin and defensin β2	(Wang et al., 2004)
	1,25(OH)₂D₃	10–100 nM	In vitro/ex vivo	RAW264.7 cells and macrophages from COX2 WT and VDR KO C57BL/6/Sv129 mice	LPS	Suppression of Akt/NF-κB/COX-2	(Wang et al., 2014)
	1,25(OH)₂D₃	50 ng (diet) or 100 nM (ex vivo)	In vivo/ex vivo	C57BL/6 WT and VDR KO mice and iNKT cells/splenocytes ex vivo	αGalCer	VDR 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)₂D₃	25-50 ng/day/mouse (diet)	In vivo	CypKO and WT C57BL/6 mice	αGalCer (intraperitoneal)	1,25(OH)₂D₃ needed for normal NKT cell development	(Yu and Cantorna, 2011)
	1,25(OH)₂D₃	2, 20, and 50 nM	In vitro	Human PBMC and THP-1 cells	LPS 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)
LXR	22(R)-hydroxy-cholesterol and 25-hydro xycholesterol	20 µl of 10 nM each ear	In vivo	CD1 and LXRα^−/−, LXRβ^−/−, LXRα/β^−/− C57Bl/6 mice	TPA-induced contact dermatitis or oxazolone-induced dermatitis	Decrease in ear thickness, inflammation of dermis and epidermis, and proinflammatory cytokines TNF-α and IL-1α	(Fowler et al., 2003)
	Cyanidin-3-O-β-glucoside	10, 20, or 40 µM	In vitro	Murine alveolar macrophages	LPS 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 cholesterol	5 µM	In vitro/ex vivo	RAW264.7 cells and macrophages from LXRαβ^+/+ mice, LXRαβ^−/− mice, or WT C57BL/6 mice	LPS 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 cholesterol	2 µM	In vitro/ex vivo	RAW264.7 cells and peritoneal macrophages from WT and LXR-null C57BL/6 mice	LPS or Escherichia coli	Inhibition of inducible NOS	(Joseph et al., 2003)
	22R-hydroxy cholesterol and 25-hydroxy cholesterol	Unspecified	In vitro	Human DCs and HepG2 cells	LPS and shRNA-LXRα	Inhibition of CCR7 expression	(Villablanca et al., 2010)
PPAR	DHA	20 µM	In vitro	RAW264.7 and Jurkat T cells	LPS or zymosan A and siRNA-PPARγ	Increased expression of M2 markers, enhanced efferocytosis, and decrease in M1 markers	(Chang et al., 2015)
	Chrysin	1–100 µM	In vitro	ANA-1, RAW264.7, HEK-293 cells, and peritoneal macrophages from obese mice	LPS, IL-4, and PPARγ-specific antagonist GW9662	Decrease in M1 markers and increase in M2 markers	(Feng et al., 2014)
	Apigenin	7.5 µM	In vitro	ANA-1, RAW264.7, HEK-293 cells, and murine primary peritoneal macrophages	LPS or IL-4, PPARγ-specific antagonist GW9662, and shRNA-PPARγ	Favoring M2 polarization via inhibition of NF-κB	(Feng et al., 2016)
	EPA	0.1, 0.5, or 1.0 g/kg i.p.	In vivo/ex vivo	C57BL/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 ether	Reduced 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 DHA	25, 50, or 100 µM	In vitro	Human PBMC, Th-cell assays	PMA,ionomycin and PPARγ-specific antagonist T0070907	Reduction of IL-2, IL-4, and TNF-α in Th cells (DHA to a lesser extent than EPA)	(Jaudszus et al., 2013)
	DHA	50 µM	In vitro	Bone marrow–derived DCs from C56BL/6 mice	LPS and PPARγ-specific antagonist GW9662	Immature DC phenotype and inhibition of IL-12 via inhibition of NF- κBp65 nuclear translocation	(Kong et al., 2010)
	EPA and DHA	10 and 100 µM	In vitro	HK-2 cells	LPS and PPARγ-specific antagonist bisphenol A diglycidyl ether	Decrease in LPS-induced MCP-1 in an NF-κB–dependent manner	(Li et al., 2005)
	PA and DHA	0.5 mM PA and 50 µM DHA	In vitro	RAW264.7 cells	LPS and PPARγ-specific antagonist GW9662	Increased M2 markers dependent on the PPAR-γ and NF-κBp65 signal pathway	(Luo et al., 2017)
	Oxidized EPA	500 µl 3.3 mM	In vivo	WT and PPARα^−/− 129SV mice	LPS	Inhibited rolling and adhesion in neutrophils and monocytes	(Sethi et al., 2002)
	EPA	100, 250, or 500 mg/kg/day i.p.	In vivo/ex vivo	BALB/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 GW9662	Prolonged 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)
	DHA	50 µM	In vitro	Monocytes (differentiated into DCs) and lymphocytes from human PBMC	Stimulation dependent on assay and PPARγ-specific antagonist GW9662	Downregulation 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

Receptor	Nutritional Activator	Concentration and Mode of Administration	Type of Study	Model	Stimulant/Disease Model	Effect	Reference
GPR41	High-fiber diet or low-fiber diet supplemented with acetylated, propionylated, or butyrylated high-amylose maize starch	Ad libitum	In vivo	WT, GPR109A^−/− and Igα^−/− C57BL6/J mice	DSS-induced colitis	Butyrate 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 propionate	200 mM acetate in drinking water or 10 nM acetate or 1 mM propionate (cell culture)	In vivo/in vitro	WT, GPR41^−/−, and GPR43^−/− C57BL/6 mice and murine intestinal cells	Induction 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 diet	Not specified	In vivo	WT and GPR41^−/− C57BL/6J mice	High-fiber diet during pregnancy and lactation	Increased 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 vivo	WT, GPR41^−/−, and GPR43^−/− C57BL/6 mice	HDM-induced allergic airway inflammation	Reduction of airway inflammation in a GPR41-dependent manner (propionate)	(Trompette et al., 2014)
GPR43	Acetate, butyrate, and propionate	10 nM acetate or propionate, 5 nM butyrate	In vitro	Mouse glomerular mesangial cells and VERSUS-40 MES 13	GPR43 overexpression and siRNA-GPR43	Inhibition of phosphorylated NF-κB and MCP-1 expression via GPR43–β-arrestin-2 pathway	(Huang et al., 2020)
	Acetate and propionate	200 mM acetate in drinking water or 10 nM acetate or 1 mM propionate (cell culture)	In vivo/in vitro	WT, GPR41^−/− and GPR43^−/− C57BL/6 mice and murine intestinal cells	Induction 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)
	Acetate	100, 200, or 300 mM in drinking water	In vivo	WT, GPR43^−/− and GPR109A^−/− C57BL/6 mice	DSS-induced colitis	Improvement of clinical scores, histologic scores, and colon length via activation of NLPR3 inflammasome dependent on GPR109A and GPR43 signaling	(Macia et al., 2015)
	Acetate	150 mM in drinking water	In vivo/ex vivo	WT, 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 colitis	Exacerbated 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)
	Acetate	10 mM	Ex vivo	Macrophages 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 propionate	10 nM	In vivo/ex vivo	Neutrophilic granulocytes (polymorphonuclear leukocytes) from WT and GPR43^−/− C57BL/6 mice	DSS-induced colitis	GPR43^−/− 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 propionate	150 mM SCFAs or propionate in drinking water	In vivo	WT, 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)
	SCFAs	0.1–100 mM	Ex vivo	Bone marrow–derived neutrophils from WT and GPR43^−/− C57BL/6 × 129 mice	—	Induction of neutrophil chemotaxis via PI3Kγ, Rac2, and MAPKs	(Vinolo et al., 2011)
	Acetate	300 mM in drinking water	In vivo	WT and GPR43^−/− C57BL/6 mice	—	Promotion of intestinal IgA via induction of Aldh1a1 in splenic dendritic cells	(Wu et al., 2017)
	Butyrate	100 mM in drinking water	In vivo and ex vivo	WT and GPR43^−/− C57BL/6 mice, and ex vivo intestinal epithelial cells	Antibiotic treatment to eliminate gut microbiota	Promotion 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)
GPR109A	Niacin	0.1 mM	In vitro	Human monocytes and TCP-1	LPS or Lysteria monocytogenes and siRNA-GPR109A	Reduction 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 starch	Ad libitum	In vivo	WT, GPR109A^−/− and Igα^−/− C57BL6/J mice	DSS-induced colitis	Butyrate 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)
	Niacin	100 µM	In vitro	Human mature blood neutrophils	Pertussis toxin, a GPR activation blocker	Acceleration of apoptosis in mature neutrophils due to less decreased cAMP leading to reduced Bad phosphorylation	(Kostylina et al., 2008)
	Acetate	100, 200, or 300 mM in drinking water	In vivo	WT, GPR43^−/− and GPR109A^−/− C57BL/6 mice	DSS-induced colitis	Improvement of clinical scores, histologic scores, and colon length via activation of NLPR3 inflammasome dependent on GPR109A and GPR43 signaling	(Macia et al., 2015)
	β-Hydroxybutyrate	100 mg/kg (administration route unknown) ketogenic diet	In vivo	WT and GPR109A^−/− C57BL/6 mice	Left middle cerebral artery occlusion	Reduction of consequences of ischemic stroke due to activation of anti-inflammatory microglia cells	(Rahman et al., 2014)
	Butyrate and niacin	25 mM in drinking water	In vivo/ex vivo	WT, IL18^−/−, Apc^-/+ and GPR109A^+/− Apc^−/− C57BL/6 mice, murine macrophages, and DCs	DSS-induced colitis and azoxymethane-induced colon cancer	GPR109A^+/− 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 butyrate	200 mM acetate, 100 mM propionate, or 100 mM butyrate in drinking water	In vivo	WT and GPR109A^−/− C57BL/6 mice	Intragastric administration of peanut extract	Enhancement of CD103⁺ DCs with increased expression of Aldh1a2 and increase in Treg populations	(Tan et al., 2016)
GPR120	DHA	30 mg/kg i.p. for in vivo and 10 µM ex vivo	In vivo and ex vivo	WT and GPR120 KO Balb/c mice	Naphthalene-induced airway injury	Accelerated resolving of airway injury by proliferation and migration of club cells	(Lee et al., 2017)
	DHA	100 µM	In vitro	RAW-264.7 cells	LPS and siRNA-GPR120	Suppression of NF-κB resulting in an anti-inflammatory response	(Liu et al., 2014)

	EPA	10, 20, or 30 mg/kg oral 20 µM (in vitro)	In vivo/in vitro	Nlpr3^−/− 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 vitro	WT 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)
	DHA	50 and 100 µM	In vitro	Human THP-1 cells and PBMC	LPS and siRNA-GPR120	Decreased NLRP3, AIM2, and NAIP/NLCR4 inflammasome activation	(Williams-Bey et al., 2014)
	DHA, EPA, and α-linolenic acid	20 µM	In vitro	Human THP-1 cells	shRNA-GPR120 and shRNA-GPR40	Inhibition of IL-1β and caspase 1 activity via NLRP3 inflammasome mediated via both GPR120 and GPR40	(Yan et al., 2013)
GPR40	Palmitic acid	100 µM	In vitro	Mouse primary hepatocytes and RAW264.7 cells	LPS and GPR40-specific antagonist GW1100	Synergistic 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 acid	200 µM oleic acid or 100 µM linoleic acid	In vitro	Human neutrophils	GPR40-specific antagonist GW1100	Increase 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 acid	50 µM	In vitro	Caco-2 and HEK293	IFN-γ and TNF-α, GPR40-specific antagonist GW1100	Improved 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)
	EPA	10, 20 or 30 mg/kg oral 20 µM (in vitro)	In vivo/in vitro	Nlpr3^−/− 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 acid	20 µM	In vitro	Human THP-1 cells	shRNA-GPR120 and shRNA-GPR40	Inhibition of IL-1β and caspase 1 activity via NLRP3 inflammasome, mediated via both GPR120 and GPR40	(Yan et al., 2013)
GPR81
	Lactate	150 µM at 30 µl/g i.p. 15 mM (in vitro)	In vivo/in vitro	C57BL/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-ARRB2	In 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)
	Lactate	10 mM	In vivo/ex vivo	Primary myometrial smooth muscle cells and uterine explants from timed-pregnant CD-1 mice, GPR81^−/−, and GPR81 knocked-down mice	Intraperitoneal injection LPS, IL-1β ex vivo	Anti-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)
T2R	Flavones (apigenin, chrysin, and wogonin)	10 µM	In vitro	A549 and 16HBE cells, and primary sinonasal epithelial cell cilia	Stimulation with phorbol 12-myristate 13-acetate, inducible NOS, or TNF-α, global PKC inhibitor Gö6983	Reduction inflammation via downregulation of IL-18, granulate colony-stimulating factor, and granulocyte macrophage colony-stimulating factor	(Hariri et al., 2017)
	Quinine	56 µM	In vitro	Human 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.

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TABLE 4

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

Receptor	Nutritional Activator	Concentration and Mode of Administration	Type of Study	Model	Stimulant/Disease Model	Effect	Reference
TLR2	Normal or Western-like rodent diet	Ad libitum	In vivo	WT and TLR2/4 double-KO C57BL6	Crossfostering and TLR4 specific inhibitor TAK-242	Maternal 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 acids	500 µM	In vitro/ex vivo	RAW264.7 cells and BMDC from WT and TLR2/4 double-KO C57BL/6 mice	RAW264.7 cells were treated with siRNA-TLR2/4	Increase in proinflammatory cytokines	(Nguyen et al., 2007)
	β2→1-fructan	1 or 100 µg/ml	In vitro	Human PBMC, THP-1 cells, and TLR2 reporter cell lines	—	Elevated IL-10/IL-12 protein levels	(Vogt et al., 2013)
	β2→1-fructan	100 mg/l	In vitro	T84 cells	Phorbol 12-myrestare 13-acetate and TLR2 blocking antibody	Improvement of intestinal epithelial barrier function	(Vogt et al., 2014)
TLR4	FOS, inulin, GOS, and goat milk oligosaccharides	0.005 –5 g/l	In vitro/ex vivo	Human peripheral blood monocytes, monocytes and lymphocytes from Wistar rats, and splenocytes from WT and TLR4^−/− C57BL/6J mice	LPS, concanavalin A, and MAPK inhibitors	NDOs 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 diet	Ad libitum	In vivo	WT and TLR2/4 double-KO C57BL6	Crossfostering and TLR4-specific inhibitor TAK-242	Maternal 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 laurate	100–500 µM	In vitro	RAW 264.7 cells, immortalized MyD88^−/− macrophages, and HEK293T cells	Bovine serum albumin and polymyxin B and TLR4-specific inhibitor TAK-242	Induction of COX-2 and TNF-α	(Huang et al., 2012)
	Sialyl(α2,3)lactose	25 mM in diet or 3 mg oral gavage	In vivo	St3gal4^−/−, IL10^−/−, St3gal4^−/−;IL10^−/− and TLR4^−/− C57BL/J6 mice	Crossfostering 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 acid	50, 75, or 100 µM	In vitro	RAW264.7 and 293T cells transfected with TLR4 and MD2	Dominant-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 FOS	5 mg/ml	In vitro	Human monocyte–derived DCs	LPS, Bifidobacterium breve, and TLR4-specific antagonist	Induction of IL-10 secretion of (Bifidobacterium breve–stimulated) DCs	(Lehmann et al., 2015)
	Palmitic acid	50–300 µM	In vitro	Human 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 acids	500 µM	In vitro/ex vivo	RAW264.7 cells and BMDC from WT and TLR2/4 double-KO C57BL/6 mice	RAW264.7 cells were treated with siRNA-TLR2/4	Increase in proinflammatory cytokines	(Nguyen et al., 2007)
	Goat milk oligosaccharides, inulin, GOS, and FOS	5 mg/ml	In vitro/ex vivo	IEC18, HT29, Caco-2 and Caco‐2/TC7 cells and colon cells from WT and TLR4 KO C57BL/6J mice	Specific inhibitors of NF-κB and MAPK pathways, shRNA specific for MyD88 and TLR4 for gene knockdown	NDOs 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 vitro	WT 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^−/− mice	Diet-induced obesity siRNA-TLR4	Diet-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)
	Palmitate	100-200 µM	In vitro/ex vivo	Coculture of 3T3-L1 and RAW264.7, Ba/F3, or TLR4 mutant peritoneal macrophages of C3H/HeJ or C3H/HeN mice	TNF-α, LPS	Role of TLR4/NF-κB pathway in SFA-induced inflammatory changes	(Suganami et al., 2007)