Toll-like receptors play a critical role in innate immunity by detecting invading pathogens. The ability of TLRs to engage different intracellular signaling molecules and cross-talk with other regulatory pathways is an important factor in shaping the type, magnitude, and duration of the inflammatory response. The present review will cover the fundamental signaling pathways utilized by TLRs and how these pathways regulate the innate immune response to pathogens. Abbreviations: TLR, Toll-like receptor; PRR, pattern recognition receptor; PAMP, pathogen-associated molecular pattern; LPS, lipopolysaccharide; APC, antigen-presenting cell; IL, interleukin; TIR, Toll/IL-1R homology; MyD88, myeloid differentiation factor 88; IFN, interferon; TRIF, TIR-domain-containing adapter-inducing interferon-β; IRAK, IL-1R-associated kinase; TAK1, TGF-β-activated kinase; TAB1, TAK1-binding protein; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B-cells; MAPK, mitogen-activated protein kinase; NLR, NOD-like receptors; LRR, leucine-rich repeats; DC, dendritic cell; PI3K, phosphoinositide 3-kinases; GSK3, glycogen synthase kinase-3; mTOR, mammalian target of rapamycin; DAF, decay-accelerating factor; IKK, IκB kinase; IRF, interferon regulatory factors; TBK1, TANK-binding kinase 1; CARD, caspase activation and recruitment domain; PYD, pyrin N-terminal homology domain; ATF, activating transcription factor; and PTEN, phosphatase and tensin homolog.
Adib-ConquyMAdrieCMoinePAsehnouneKFittingCPinskyMR. (2000). NF-kappaB expression in mononuclear cells of patients with sepsis resembles that observed in lipopolysaccharide tolerance. Am J Respir Crit Care Med162:1877-1883.
2.
AgostiniLMartinonFBurnsKMcDermottMFHawkinsPNTschoppJ (2004). NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity20:319-325.
3.
AndroulidakiAIliopoulosDArranzADoxakiCSchworerSZacharioudakiV. (2009). The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs. Immunity31:220-231.
4.
ArbibeLMiraJPTeuschNKlineLGuhaMMackmanN. (2000). Toll-like receptor 2-mediated NF-kappa B activation requires a Rac1-dependent pathway. Nat Immunol1:533-540.
5.
BiswasSKLopez-CollazoE (2009). Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol30:475-487.
BiswasSKBistPDhillonMKKajijiTDel FresnoCYamamotoM. (2007). Role for MyD88-independent, TRIF pathway in lipid A/TLR4-induced endotoxin tolerance. J Immunol179:4083-4092.
8.
CantleyLC (2002). The phosphoinositide 3-kinase pathway. Science296:1655-1657.
9.
CaoZXiongJTakeuchiMKuramaTGoeddelDV (1996). TRAF6 is a signal transducer for interleukin-1. Nature383:443-446.
10.
CavaillonJMAdib-ConquyM (2006). Bench-to-bedside review: endotoxin tolerance as a model of leukocyte reprogramming in sepsis. Crit Care10:233.
11.
ChamaillardMHashimotoMHorieYMasumotoJQiuSSaabL. (2003). An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol4:702-707.
12.
ChenZJ (2005). Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol7:758-765.
13.
del FresnoCGarcia-RioFGomez-PinaVSoares-SchanoskiAFernandez-RuizIJuradoT. (2009). Potent phagocytic activity with impaired antigen presentation identifying lipopolysaccharide-tolerant human monocytes: demonstration in isolated monocytes from cystic fibrosis patients. J Immunol182:6494-6507.
DobrovolskaiaMAVogelSN (2002). Toll receptors, CD14, and macrophage activation and deactivation by LPS. Microbes Infect4:903-914.
16.
DoyleSVaidyaSO’ConnellRDadgostarHDempseyPWuT. (2002). IRF3 mediates a TLR3/TLR4-specific antiviral gene program. Immunity17:251-263.
17.
FitzgeraldKAPalsson-McDermottEMBowieAGJefferiesCAMansellASBradyG. (2001). Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature413:78-83.
18.
FrameSCohenPBiondiRM (2001). A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol Cell7:1321-1327.
19.
FukaoTYamadaTTanabeMTerauchiYOtaTTakayamaT. (2002a). Selective loss of gastrointestinal mast cells and impaired immunity in PI3K-deficient mice. Nat Immunol3:295-304.
20.
FukaoTTanabeMTerauchiYOtaTMatsudaSAsanoT. (2002b). PI3K-mediated negative feedback regulation of IL-12 production in DCs. Nat Immunol3:875-881.
21.
GhoshSMayMJKoppEB (1998). NF-κB and rel proteins: evolutionary conserved mediators of immune responses. Annu Rev Immunol16: 225-260.
22.
GilchristMThorssonVLiBRustAGKorbMRoachJC. (2006). Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4. Nature441:173-178.
23.
GirardinSEBonecaIGCarneiroLAAntignacAJehannoMVialaJ. (2003). Nod1 detects a unique muropeptide from Gram-negative bacterial peptidoglycan. Science300:1584-1587.
24.
GuhaMMackmanN (2002). The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells. J Biol Chem277:32124-32132.
25.
GulatiPGaspersLDDannSGJoaquinMNobukuniTNattF. (2008). Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34. Cell Metab7:456-465.
26.
HackerHRedeckeVBlagoevBKratchmarovaIHsuLCWangGG. (2006). Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature439:204-207.
27.
HajishengallisGLambrisJD (2010). Crosstalk pathways between Toll-like receptors and the complement system. Trends Immunol31:154-163.
28.
HajishengallisGTappingRIHarokopakisENishiyamaSRattiPSchifferleRE. (2006a). Differential interactions of fimbriae and lipopolysaccharide from Porphyromonas gingivalis with the Toll-like receptor 2-centred pattern recognition apparatus. Cell Microbiol8:1557-1570.
29.
HajishengallisGWangMHarokopakisETriantafilouMTriantafilouK (2006b). Porphyromonas gingivalis fimbriae proactively modulate b2 integrin adhesive activity and promote binding to and internalization by macrophages. Infect Immun74:5658-5666.
30.
HajishengallisGShakhatrehMAWangMLiangS (2007). Complement receptor 3 blockade promotes IL-12-mediated clearance of Porphyromonas gingivalis and negates its virulence in vivo. J Immunol179:2359-2367.
HajishengallisGWangMLiangS (2009). Induction of distinct TLR2-mediated proinflammatory and proadhesive signaling pathways in response to Porphyromonas gingivalis fimbriae. J Immunol182: 6690-6696.
33.
HarokopakisEHajishengallisG (2005). Integrin activation by bacterial fimbriae through a pathway involving CD14, Toll-like receptor 2, and phosphatidylinositol-3-kinase. Eur J Immunol35:1201-1210.
34.
HasanUChaffoisCGaillardCSaulnierVMerckETancrediS. (2005). Human TLR10 is a functional receptor, expressed by B cells and plasmacytoid dendritic cells, which activates gene transcription through MyD88. J Immunol174:2942-2950.
35.
HorngTBartonGMMedzhitovR (2001). TIRAP: an adapter molecule in the Toll signaling pathway. Nat Immunol2:835-841.
36.
HorngTBartonGMFlavellRAMedzhitovR (2002). The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature420:329-333.
37.
HuXPaikPKChenJYarilinaAKockeritzLLuTT. (2006). IFN-gamma suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteins. Immunity24:563-574.
KawaiTAdachiOOgawaTTakedaKAkiraS (1999). Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity11:115-122.
43.
KimSElkonKBMaX (2004). Transcriptional suppression of interleukin-12 gene expression following phagocytosis of apoptotic cells. Immunity21:643-653.
44.
KumarHKawaiTAkiraS (2009a). Pathogen recognition in the innate immune response. Biochem J420:1-16.
45.
KumarHKawaiTAkiraS (2009b). Toll-like receptors and innate immunity. Biochem Biophys Res Commun388:621-625.
46.
KuwataHMatsumotoMAtarashiKMorishitaHHirotaniTKogaR. (2006). IkappaBNS inhibits induction of a subset of Toll-like receptor-dependent genes and limits inflammation. Immunity24:41-51.
47.
LiLCousartSHuJMcCallCE (2000). Characterization of interleukin-1 receptor-associated kinase in normal and endotoxin-tolerant cells. J Biol Chem275:23340-23345.
48.
LiSStrelowAFontanaEJWescheH (2002). IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase. Proc Natl Acad Sci USA99:5567-5572.
49.
LowellCA (2006). Rewiring phagocytic signal transduction. Immunity24:243-245.
50.
MansellASmithRDoyleSLGrayPFennerJECrackPJ. (2006). Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation. Nat Immunol7:148-155.
51.
MariathasanSNewtonKMonackDMVucicDFrenchDMLeeWP. (2004). Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature430:213-218.
52.
MariathasanSWeissDSNewtonKMcBrideJO’RourkeKRoose-GirmaM. (2006). Cryopyrin activates the inflammasome in response to toxins and ATP. Nature440:228-232.
53.
MartinMSchifferleRECuestaNVogelSNKatzJMichalekSM (2003). Role of the phosphatidylinositol 3 kinase-Akt pathway in the regulation of IL-10 and IL-12 by Porphyromonas gingivalis lipopolysaccharide. J Immunol171:717-725.
54.
MartinMRehaniKJopeRSMichalekSM (2005). Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat Immunol6:777-784.
55.
MedvedevAEKopydlowskiKMVogelSN (2000). Inhibition of lipopolysaccharide-induced signal transduction in endotoxin-tolerized mouse macrophages: dysregulation of cytokine, chemokine, and Toll-like receptor 2 and 4 gene expression. J Immunol164:5564-5574.
56.
MedvedevAELentschatAWahlLMGolenbockDTVogelSN (2002). Dysregulation of LPS-induced Toll-like receptor 4-MyD88 complex formation and IL-1 receptor-associated kinase 1 activation in endotoxin-tolerant cells. J Immunol169:5209-5216.
57.
MedzhitovRPreston-HurlburtPJanewayCA (1997). A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature388:394-397.
58.
MedzhitovRPreston-HurlburtPKoppEStadlenAChenCGhoshS. (1998). MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell2:253-258.
59.
MevorachDMascarenhasJOGershovDElkonKB (1998). Complement-dependent clearance of apoptotic cells by human macrophages. J Exp Med188:2313-2320.
60.
MonneretGFinckMEVenetFDebardALBoheJBienvenuJ. (2004). The anti-inflammatory response dominates after septic shock: association of low monocyte HLA-DR expression and high interleukin-10 concentration. Immunol Lett95:193-198.
61.
MorelliAELarreginaATShufeskyWJZahorchakAFLogarAJPapworthGD. (2003). Internalization of circulating apoptotic cells by splenic marginal zone dendritic cells: dependence on complement receptors and effect on cytokine production. Blood101:611-620.
62.
MuzioMNiJFengPDixitVM (1997). IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling. Science278:1612-1615.
63.
NakagawaRNakaTTsutsuiHFujimotoMKimuraAAbeT. (2002). SOCS-1 participates in negative regulation of LPS responses. Immunity17:677-687.
64.
NegishiHOhbaYYanaiHTakaokaAHonmaKYuiK. (2005). Negative regulation of Toll-like-receptor signaling by IRF-4. Proc Natl Acad Sci USA102:15989-15994.
65.
OhtaniMNagaiSKondoSMizunoSNakamuraKTanabeM. (2008). Mammalian target of rapamycin and glycogen synthase kinase 3 differentially regulate lipopolysaccharide-induced interleukin-12 production in dendritic cells. Blood112:635-643.
66.
PiaoWSongCChenHWahlLMFitzgeraldKAO’NeillLA. (2008). Tyrosine phosphorylation of MyD88 adapter-like (Mal) is critical for signal transduction and blocked in endotoxin tolerance. J Biol Chem283:3109-3119.
67.
PopadiakKPotempaJRiesbeckKBlomAM (2007). Biphasic effect of gingipains from Porphyromonas gingivalis on the human complement system. J Immunol178:7242-7250.
68.
RauhMJHoVPereiraCShamASlyLMLamV. (2005). SHIP represses the generation of alternatively activated macrophages. Immunity23:361-374.
69.
ReFStromingerJL (2001). Toll-like receptor 2 (TLR2) and TLR4 differentially activate human dendritic cells. J Biol Chem276:37692-37699.
70.
RheeSHKimHMoyerMPPothoulakisC (2006). Role of MyD88 in phosphatidylinositol 3-kinase activation by flagellin/Toll-like receptor 5 engagement in colonic epithelial cells. J Biol Chem281:18560-18568.
71.
Santos-SierraSDeshmukhSDKalnitskiJKuenziPWymannMPGolenbockDT. (2009). Mal connects TLR2 to PI3Kinase activation and phagocyte polarization. EMBO J28:2018-2027.
72.
SarkarSNPetersKLElcoCPSakamotoSPalSSenGC (2004). Novel roles of TLR3 tyrosine phosphorylation and PI3 kinase in double-stranded RNA signaling. Nat Struct Mol Biol11:1060-1067.
73.
SchabbauerGTencatiMPedersenBPawlinskiRMackmanN (2004). PI3K-Akt pathway suppresses coagulation and inflammation in endotoxemic mice. Arterioscler Thromb Vasc Biol24:1963-1969.
74.
ShinoharaHInoueAToyama-SorimachiNNagaiYYasudaTSuzukiH. (2005). Dok-1 and Dok-2 are negative regulators of lipopolysaccharide-induced signaling. J Exp Med201:333-339.
75.
SlyLMRauhMJKalesnikoffJSongCHKrystalG (2004). LPS-induced upregulation of SHIP is essential for endotoxin tolerance. Immunity21:227-239.
76.
TakeuchiOKawaiTSanjoHCopelandNGGilbertDJJenkinsNA. (1999). TLR6: a novel member of an expanding Toll-like receptor family. Gene231:59-65.
77.
TakeuchiOKawaiTMuhlradtPFMorrMRadolfJDZychlinskyA. (2001). Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int Immunol13:933-940.
78.
TakeuchiOSatoSHoriuchiTHoshinoKTakedaKDongZ. (2002). Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins. J Immunol169:10-14.
79.
TschoppJMartinonFBurnsK (2003). NALPs: a novel protein family involved in inflammation. Nat Rev Mol Cell Biol4:95-104.
80.
TsengPHMatsuzawaAZhangWMinoTVignaliDAKarinM (2010). Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines. Nat Immunol11:70-75.
81.
TurnquistHRCardinalJMacedoCRosboroughBRSumpterTLGellerDA. (2010). mTOR and GSK-3 shape the CD4+ T cell stimulatory and differentiation capacity of myeloid DC following exposure to LPS. Blood115:4758-4769.
82.
VerbovetskiIBychkovHTrahtembergUShapiraIHareuveniMBen-TalO. (2002). Opsonization of apoptotic cells by autologous iC3b facilitates clearance by immature dendritic cells, down-regulates DR and CD86, and up-regulates CC chemokine receptor 7. J Exp Med196:1553-1561.
WangCDengLHongMAkkarajuGRInoueJChenZJ (2001). TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature412:346-351.
85.
WangMShakhatrehMAJamesDLiangSNishiyamaSYoshimuraF. (2007). Fimbrial proteins of Porphyromonas gingivalis mediate in vivo virulence and exploit TLR2 and complement receptor 3 to persist in macrophages. J Immunol179:2349-2358.
86.
WangMKraussJLDomonHHosurKBLiangSMagottiP. (2010). Microbial hijacking of complement-Toll-like receptor crosstalk. Sci Signal3:ra11.
87.
WangYTangYTengLWuYZhaoXPeiG (2006). Association of beta-arrestin and TRAF6 negatively regulates Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol7:139-147.
88.
WeichhartTCostantinoGPoglitschMRosnerMZeydaMStuhlmeierKM. (2008). The TSC-mTOR signaling pathway regulates the innate inflammatory response. Immunity29:565-577.
89.
WingroveJADiScipioRGChenZPotempaJTravisJHugliTE (1992). Activation of complement components C3 and C5 by a cysteine proteinase (gingipain-1) from Porphyromonas (Bacteroides) gingivalis. J Biol Chem267:18902-18907.
90.
WolkKDockeWDvon BaehrVVolkHDSabatR (2000). Impaired antigen presentation by human monocytes during endotoxin tolerance. Blood96:218-223.
91.
WolkKKunzSCromptonNEVolkHDSabatR (2003). Multiple mechanisms of reduced major histocompatibility complex class II expression in endotoxin tolerance. J Biol Chem278:18030-18036.
92.
WrightSDSilversteinSC (1983). Receptors for C3b and C3bi promote phagocytosis but not the release of toxic oxygen from human phagocytes. J Exp Med158:2016-2023.
93.
YamamotoMSatoSHemmiHHoshinoKKaishoTSanjoH. (2003a). Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science301:640-643.
94.
YamamotoMSatoSHemmiHUematsuSHoshinoKKaishoT. (2003b). TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol4:1144-1150.
ZhangHHLipovskyAIDibbleCCSahinMManningBD (2006). S6K1 regulates GSK3 under conditions of mTOR-dependent feedback inhibition of Akt. Mol Cell24:185-197.
97.
Ziegler-HeitbrockL (2001). The p50-homodimer mechanism in tolerance to LPS. J Endotoxin Res7:219-222.
