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2000
Volume 26, Issue 4
  • ISSN: 1389-2037
  • E-ISSN: 1875-5550

Abstract

TLR4 stands at the forefront of innate immune responses, recognizing various pathogen-associated molecular patterns and endogenous ligands, thus serving as a pivotal mediator in the immune system's defense against infections and tissue damage. Beyond its canonical role in infection, emerging evidence highlights TLR4's involvement in numerous non-infectious human diseases, ranging from metabolic disorders to neurodegenerative conditions and cancer. Targeting TLR4 signaling pathways presents a promising therapeutic approach with broad applicability across these diverse pathological states. In metabolic disorders such as obesity and diabetes, dysregulated TLR4 activation contributes to chronic low-grade inflammation and insulin resistance, driving disease progression. In cardiovascular diseases, TLR4 signaling promotes vascular inflammation and atherogenesis, implicating its potential as a therapeutic target to mitigate cardiovascular risk. Neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, exhibit aberrant TLR4 activation linked to neuroinflammation and neuronal damage, suggesting TLR4 modulation as a strategy to attenuate neurodegeneration.

Additionally, in cancer, TLR4 signaling within the tumor microenvironment promotes tumor progression, metastasis, and immune evasion, underscoring its relevance as a target for anticancer therapy. Advances in understanding TLR4 signaling cascades and their contributions to disease pathogenesis have spurred the development of various pharmacological agents targeting TLR4. These agents range from small molecule inhibitors to monoclonal antibodies, with some undergoing preclinical and clinical evaluations. Furthermore, strategies involving TLR4 modulation through dietary interventions and microbiota manipulation offer additional avenues for therapeutic exploration. Hence, targeting TLR4 holds significant promise as a therapeutic strategy across a spectrum of human diseases, offering the potential to modulate inflammation, restore immune homeostasis, and impede disease progression.

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2024-12-24
2025-04-18
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References

  1. PłóciennikowskaA. Hromada-JudyckaA. BorzęckaK. KwiatkowskaK. Co-operation of TLR4 and raft proteins in LPS-induced pro-inflammatory signaling.Cell. Mol. Life Sci.201572355758110.1007/s00018‑014‑1762‑525332099
    [Google Scholar]
  2. RochaD.M. CaldasA.P. OliveiraL.L. BressanJ. HermsdorffH.H. Saturated fatty acids trigger TLR4-mediated inflammatory response.Atherosclerosis201624421121510.1016/j.atherosclerosis.2015.11.01526687466
    [Google Scholar]
  3. ZhangY. LiangX. BaoX. XiaoW. ChenG. Toll-like receptor 4 (TLR4) inhibitors: Current research and prospective.Eur. J. Med. Chem.202223511429110.1016/j.ejmech.2022.11429135307617
    [Google Scholar]
  4. FirmalP. ShahV.K. ChattopadhyayS. Insight into TLR4-mediated immunomodulation in normal pregnancy and related disorders.Front. Immunol.20201180710.3389/fimmu.2020.0080732508811
    [Google Scholar]
  5. McGettrickA.F. O’NeillL.A.J. Toll-like receptors: Key activators of leucocytes and regulator of haematopoiesis.Br. J. Haematol.2007139218519310.1111/j.1365‑2141.2007.06802.x17897294
    [Google Scholar]
  6. KhanmohammadiS. RezaeiN. Role of Toll-like receptors in the pathogenesis of COVID-19.J. Med. Virol.20219352735273910.1002/jmv.2682633506952
    [Google Scholar]
  7. KrügerC.L. ZeunerM.T. CottrellG.S. WideraD. HeilemannM. Quantitative single-molecule imaging of TLR4 reveals ligand-specific receptor dimerization.Sci. Signal.201710503eaan130810.1126/scisignal.aan130829089449
    [Google Scholar]
  8. JiangZ. GeorgelP. DuX. ShamelL. SovathS. MuddS. HuberM. KalisC. KeckS. GalanosC. FreudenbergM. BeutlerB. CD14 is required for MyD88-independent LPS signaling.Nat. Immunol.20056656557010.1038/ni120715895089
    [Google Scholar]
  9. BrunoK. WollerS.A. MillerY.I. YakshT.L. WallaceM. BeatonG. ChakravarthyK. Targeting toll-like receptor-4 (TLR4)—an emerging therapeutic target for persistent pain states.Pain2018159101908191510.1097/j.pain.000000000000130629889119
    [Google Scholar]
  10. KarinM. Ben-NeriahY. Phosphorylation meets ubiquitination: The control of NF-[kappa]B activity.Annu. Rev. Immunol.200018162166310.1146/annurev.immunol.18.1.62110837071
    [Google Scholar]
  11. CollinsT. ReadM.A. NeishA.S. WhitleyM.Z. ThanosD. ManiatisT. Transcriptional regulation of endothelial cell adhesion molecules: NF-κB and cytokine-inducible enhancers.FASEB J.199591089990910.1096/fasebj.9.10.75422147542214
    [Google Scholar]
  12. TsuchiyaH. NakanoR. KonnoT. OkabayashiK. NaritaT. SugiyaH. Activation of MEK/ERK pathways through NF-κB activation is involved in interleukin-1β-induced cyclooxygenease-2 expression in canine dermal fibroblasts.Vet. Immunol. Immunopathol.20151683-422323210.1016/j.vetimm.2015.10.00326549149
    [Google Scholar]
  13. MoghimpourB.F. VallejoJ.G. RezaeiN. Toll-like receptor signaling pathways in cardiovascular diseases: Challenges and opportunities.Int. Rev. Immunol.201231537939510.3109/08830185.2012.70676123083347
    [Google Scholar]
  14. MohyuddinS.G. QamarA. HuC. ChenS.W. WenJ. LiuX. MaX. YuZ. YongY. WuL.Y. BaoM.L. JuX.H. Effect of chitosan on blood profile, inflammatory cytokines by activating TLR4/NF-κB signaling pathway in intestine of heat stressed mice.Sci. Rep.20211112060810.1038/s41598‑021‑98931‑834663855
    [Google Scholar]
  15. YuL. YinM. YangX. LuM. TangF. WangH. Calpain inhibitor I attenuates atherosclerosis and inflammation in atherosclerotic rats through eNOS/NO/NF-κB pathway.Can. J. Physiol. Pharmacol.2018961606710.1139/cjpp‑2016‑065228758430
    [Google Scholar]
  16. ChengA. HanC. FangX. SunJ. ChenX. WanF. Extractable and non-extractable polyphenols from blueberries modulate LPS -induced expression of iNOS and COX -2 in RAW264. 7 macrophages via the NF-κB signalling pathway.J. Sci. Food Agric.201696103393340010.1002/jsfa.751926538333
    [Google Scholar]
  17. FunamiK. MatsumotoM. OshiumiH. InagakiF. SeyaT. Functional interfaces between TICAM-2/TRAM and TICAM-1/TRIF in TLR4 signaling.Biochem. Soc. Trans.201745492993510.1042/BST2016025928630139
    [Google Scholar]
  18. MarongiuL. GornatiL. ArtusoI. ZanoniI. GranucciF. Below the surface: The inner lives of TLR4 and TLR9.J. Leukoc. Biol.2019106114716010.1002/JLB.3MIR1218‑483RR30900780
    [Google Scholar]
  19. LiuS. CaiX. WuJ. CongQ. ChenX. LiT. DuF. RenJ. WuY.T. GrishinN.V. ChenZ.J. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation.Science20153476227aaa263010.1126/science.aaa263025636800
    [Google Scholar]
  20. UllahM.O. SweetM.J. MansellA. KellieS. KobeB. TRIF-dependent TLR signaling, its functions in host defense and inflammation, and its potential as a therapeutic target.J. Leukoc. Biol.20161001274510.1189/jlb.2RI1115‑531R27162325
    [Google Scholar]
  21. LukheleS. BoukhaledG.M. BrooksD.G. Type I interferon signaling, regulation and gene stimulation in chronic virus infection.Semin. Immunol.20194310127710.1016/j.smim.2019.05.00131155227
    [Google Scholar]
  22. Cusson-HermanceN. KhuranaS. LeeT.H. FitzgeraldK.A. KelliherM.A. Rip1 mediates the Trif-dependent Toll-like receptor 3- and 4-induced NF-kappaB activation but does not contribute to interferon regulatory factor 3 activation.J. Biol. Chem.200528044365603656610.1074/jbc.M50683120016115877
    [Google Scholar]
  23. SatoS. SugiyamaM. YamamotoM. WatanabeY. KawaiT. TakedaK. AkiraS. Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling.J. Immunol.200317184304431010.4049/jimmunol.171.8.430414530355
    [Google Scholar]
  24. WolfD. LeyK. Immunity and inflammation in atherosclerosis.Circ. Res.2019124231532710.1161/CIRCRESAHA.118.31359130653442
    [Google Scholar]
  25. ChildsB.G. BakerD.J. WijshakeT. ConoverC.A. CampisiJ. van DeursenJ.M. Senescent intimal foam cells are deleterious at all stages of atherosclerosis.Science2016354631147247710.1126/science.aaf665927789842
    [Google Scholar]
  26. StaryH.C. ChandlerA.B. GlagovS. GuytonJ.R. InsullW.Jr RosenfeldM.E. SchafferS.A. SchwartzC.J. WagnerW.D. WisslerR.W. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the committee on vascular lesions of the council on arteriosclerosis, American heart association.Circulation19948952462247810.1161/01.CIR.89.5.24628181179
    [Google Scholar]
  27. VorobjevaN.V. ChernyakB.V. NETosis: Molecular mechanisms, role in physiology and pathology.Biochemistry (Mosc.)202085101178119010.1134/S000629792010006533202203
    [Google Scholar]
  28. LiuY. Carmona-RiveraC. MooreE. SetoN.L. KnightJ.S. PryorM. YangZ.H. HemmersS. RemaleyA.T. MowenK.A. KaplanM.J. Myeloid-specific deletion of peptidylarginine deiminase 4 mitigates atherosclerosis.Front. Immunol.20189168010.3389/fimmu.2018.0168030140264
    [Google Scholar]
  29. YangM. ChenQ. MeiL. WenG. AnW. ZhouX. NiuK. LiuC. RenM. SunK. XiaoQ. ZhangL. Neutrophil elastase promotes neointimal hyperplasia by targeting Toll-like receptor 4 (TLR4)–NF-κB signalling.Br. J. Pharmacol.2021178204048406810.1111/bph.1558334076894
    [Google Scholar]
  30. TsourouktsoglouT.D. WarnatschA. IoannouM. HovingD. WangQ. PapayannopoulosV. Histones, DNA, and citrullination promote neutrophil extracellular trap inflammation by regulating the localization and activation of TLR4.Cell Rep.202031510760210.1016/j.celrep.2020.10760232375035
    [Google Scholar]
  31. DurhamA.L. SpeerM.Y. ScatenaM. GiachelliC.M. ShanahanC.M. Role of smooth muscle cells in vascular calcification: Implications in atherosclerosis and arterial stiffness.Cardiovasc. Res.2018114459060010.1093/cvr/cvy01029514202
    [Google Scholar]
  32. ZhaiM. GongS. LuanP. ShiY. KouW. ZengY. ShiJ. YuG. HouJ. YuQ. JianW. ZhuangJ. FeinbergM.W. PengW. Extracellular traps from activated vascular smooth muscle cells drive the progression of atherosclerosis.Nat. Commun.2022131750010.1038/s41467‑022‑35330‑136473863
    [Google Scholar]
  33. WuH. WangY. ZhangY. XuF. ChenJ. DuanL. ZhangT. WangJ. ZhangF. Breaking the vicious loop between inflammation, oxidative stress and coagulation, a novel anti-thrombus insight of nattokinase by inhibiting LPS-induced inflammation and oxidative stress.Redox Biol.20203210150010.1016/j.redox.2020.10150032193146
    [Google Scholar]
  34. JacksonS.P. DarboussetR. SchoenwaelderS.M. Thromboinflammation: Challenges of therapeutically targeting coagulation and other host defense mechanisms.Blood2019133990691810.1182/blood‑2018‑11‑88299330642917
    [Google Scholar]
  35. LeviM. van der PollT. BüllerH.R. Bidirectional relation between inflammation and coagulation.Circulation2004109222698270410.1161/01.CIR.0000131660.51520.9A15184294
    [Google Scholar]
  36. SzabaF.M. SmileyS.T. Roles for thrombin and fibrin(ogen) in cytokine/chemokine production and macrophage adhesion in vivo.Blood20029931053105910.1182/blood.V99.3.105311807012
    [Google Scholar]
  37. Di LorenzoF. KubikŁ. OblakA. LorèN.I. CiganaC. LanzettaR. ParrilliM. HamadM.A. De SoyzaA. SilipoA. JeralaR. BragonziA. ValvanoM.A. Martín-SantamaríaS. MolinaroA. Activation of human Toll-like receptor 4 (TLR4)·myeloid differentiation factor 2 (MD-2) by hypoacylated lipopolysaccharide from a clinical isolate of Burkholderia cenocepacia.J. Biol. Chem.201529035213052131910.1074/jbc.M115.64908726160169
    [Google Scholar]
  38. KawaiT. AkiraS. Toll-like receptor downstream signaling.Arthritis Res.200571121910.1186/ar146915642149
    [Google Scholar]
  39. YuY. GeN. XieM. SunW. BurlingameS. PassA.K. NuchternJ.G. ZhangD. FuS. SchneiderM.D. FanJ. YangJ. Phosphorylation of Thr-178 and Thr-184 in the TAK1 T-loop is required for interleukin (IL)-1-mediated optimal NFkappaB and AP-1 activation as well as IL-6 gene expression.J. Biol. Chem.200828336244972450510.1074/jbc.M80282520018617512
    [Google Scholar]
  40. SmileyS.T. KingJ.A. HancockW.W. Fibrinogen stimulates macrophage chemokine secretion through toll-like receptor 4.J. Immunol.200116752887289410.4049/jimmunol.167.5.288711509636
    [Google Scholar]
  41. HuaF. RenW. ZhuL. Plasminogen activator inhibitor type-1 deficiency exaggerates LPS-induced acute lung injury through enhancing Toll-like receptor 4 signaling pathway.Blood Coagul. Fibrinolysis201122648048610.1097/MBC.0b013e328346ef5621577093
    [Google Scholar]
  42. MinL WangH QiH. Astragaloside IV inhibits the progression of liver cancer by modulating macrophage polarization through the TLR4/NF-κB/STAT3 signaling pathway.Am J Transl Res.202214315511566
    [Google Scholar]
  43. Vesga-JiménezD.J. MartinC. BarretoG.E. Aristizábal-PachónA.F. PinzónA. GonzálezJ. Fatty acids: An insight into the pathogenesis of neurodegenerative diseases and therapeutic potential.Int. J. Mol. Sci.2022235257710.3390/ijms2305257735269720
    [Google Scholar]
  44. RenW. WangZ. HuaF. ZhuL. Plasminogen activator inhibitor-1 regulates LPS-induced TLR4/MD-2 pathway activation and inflammation in alveolar macrophages.Inflammation201538138439310.1007/s10753‑014‑0042‑825342286
    [Google Scholar]
  45. DörgeH. NeumannT. BehrendsM. SkyschallyA. SchulzR. KasperC. ErbelR. HeuschG. Perfusion-contraction mismatch with coronary microvascular obstruction: Role of inflammation.Am. J. Physiol. Heart Circ. Physiol.20002796H2587H259210.1152/ajpheart.2000.279.6.H258711087208
    [Google Scholar]
  46. O’NeillL.A.J. BowieA.G. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling.Nat. Rev. Immunol.20077535336410.1038/nri207917457343
    [Google Scholar]
  47. HuangZ. ZhuangX. XieC. HuX. DongX. GuoY. LiS. LiaoX. Exogenous hydrogen sulfide attenuates high glucose-induced cardiotoxicity by inhibiting NLRP3 inflammasome activation by suppressing TLR4/NF-κB pathway in H9c2 cells.Cell. Physiol. Biochem.20164061578159010.1159/00045320827997926
    [Google Scholar]
  48. SuQ. LiL. SunY. YangH. YeZ. ZhaoJ. Effects of the TLR4/Myd88/NF-κB signaling pathway on NLRP3 inflammasome in coronary microembolization-induced myocardial injury.Cell. Physiol. Biochem.20184741497150810.1159/00049086629940584
    [Google Scholar]
  49. UpadhayayS. GuptaR. SinghS. MundkarM. SinghG. KumarP. Involvement of the G-Protein-Coupled Estrogen Receptor-1 (GPER) signaling pathway in neurodegenerative disorders: A review.Cell. Mol. Neurobiol.20234351833184710.1007/s10571‑022‑01301‑936307605
    [Google Scholar]
  50. WangX. LuY. SunY. HeW. LiangJ. LiL. TAK-242 protects against apoptosis in coronary microembolization-induced myocardial injury in rats by suppressing TLR4/NF-κB signaling pathway.Cell. Physiol. Biochem.20174141675168310.1159/00047124828359050
    [Google Scholar]
  51. FanC. TangX. YeM. ZhuG. DaiY. YaoZ. YaoX. Qi-Li-Qiang-Xin alleviates isoproterenol-induced myocardial injury by inhibiting excessive autophagy via activating AKT/mTOR pathway.Front. Pharmacol.201910132910.3389/fphar.2019.0132931780944
    [Google Scholar]
  52. LiuR. ZhangH.B. YangJ. WangJ.R. LiuJ.X. LiC.L. Curcumin alleviates isoproterenol-induced cardiac hypertrophy and fibrosis through inhibition of autophagy and activation of mTOR.Eur. Rev. Med. Pharmacol. Sci.201822217500750830468499
    [Google Scholar]
  53. ThangaiyanR. RobertB.M. ArjunanS. GovindasamyK. NagarajanR.P. Preventive effect of apigenin against isoproterenol-induced apoptosis in cardiomyoblasts.J. Biochem. Mol. Toxicol.20183211e2221310.1002/jbt.2221330152906
    [Google Scholar]
  54. KumariS. KatareP.B. ElancheranR. NizamiH.L. ParameshaB. AravaS. SarmaP.P. KumarR. MahajanD. KumarY. DeviR. BanerjeeS.K. Musa balbisiana fruit rich in polyphenols attenuates isoproterenol-induced cardiac hypertrophy in rats via inhibition of inflammation and oxidative stress.Oxid. Med. Cell. Longev.2020202011410.1155/2020/714749832082481
    [Google Scholar]
  55. LiaoM. XieQ. ZhaoY. YangC. LinC. WangG. LiuB. ZhuL. Main active components of Si-Miao-Yong-An decoction (SMYAD) attenuate autophagy and apoptosis via the PDE5A-AKT and TLR4-NOX4 pathways in isoproterenol (ISO)-induced heart failure models.Pharmacol. Res.202217610607710.1016/j.phrs.2022.10607735026404
    [Google Scholar]
  56. ChenX. XuS. ZhaoC. LiuB. Role of TLR4/NADPH oxidase 4 pathway in promoting cell death through autophagy and ferroptosis during heart failure.Biochem. Biophys. Res. Commun.20195161374310.1016/j.bbrc.2019.06.01531196626
    [Google Scholar]
  57. WuL. JiaM. XiaoL. WangZ. YaoR. ZhangY. GaoL. TRIM-containing 44 aggravates cardiac hypertrophy via TLR4/NOX4-induced ferroptosis.J. Mol. Med. (Berl.)2023101668569710.1007/s00109‑023‑02318‑337119283
    [Google Scholar]
  58. RheeS.H. HwangD. Murine TOLL-like receptor 4 confers lipopolysaccharide responsiveness as determined by activation of NF kappa B and expression of the inducible cyclooxygenase.J. Biol. Chem.200027544340353404010.1074/jbc.M00738620010952994
    [Google Scholar]
  59. del ZoppoG. GinisI. HallenbeckJ.M. IadecolaC. WangX. FeuersteinG.Z. Inflammation and stroke: Putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia.Brain Pathol.20001019511210.1111/j.1750‑3639.2000.tb00247.x10668900
    [Google Scholar]
  60. CasoJ.R. PradilloJ.M. HurtadoO. LorenzoP. MoroM.A. LizasoainI. Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke.Circulation2007115121599160810.1161/CIRCULATIONAHA.106.60343117372179
    [Google Scholar]
  61. LehnardtS. LachanceC. PatriziS. LefebvreS. FollettP.L. JensenF.E. RosenbergP.A. VolpeJ.J. VartanianT. The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS.J. Neurosci.20022272478248610.1523/JNEUROSCI.22‑07‑02478.200211923412
    [Google Scholar]
  62. KolA. SukhovaG.K. LichtmanA.H. LibbyP. Chlamydial heat shock protein 60 localizes in human atheroma and regulates macrophage tumor necrosis factor-alpha and matrix metalloproteinase expression.Circulation199898430030710.1161/01.CIR.98.4.3009711934
    [Google Scholar]
  63. HoppS. NolteM.W. StetterC. KleinschnitzC. SirénA.L. Albert-WeissenbergerC. Alleviation of secondary brain injury, posttraumatic inflammation, and brain edema formation by inhibition of factor XIIa.J. Neuroinflammation20171413910.1186/s12974‑017‑0815‑828219400
    [Google Scholar]
  64. SinhaS.P. AvcuP. SpieglerK.M. KomaravoluS. KimK. CominskiT. ServatiusR.J. PangK.C.H. Startle suppression after mild traumatic brain injury is associated with an increase in pro-inflammatory cytokines, reactive gliosis and neuronal loss in the caudal pontine reticular nucleus.Brain Behav. Immun.20176135336410.1016/j.bbi.2017.01.00628089558
    [Google Scholar]
  65. McKeeC.A. LukensJ.R. Emerging roles for the immune system in traumatic brain injury.Front. Immunol.2016755610.3389/fimmu.2016.0055627994591
    [Google Scholar]
  66. CorriganF. ManderK.A. LeonardA.V. VinkR. Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation.J. Neuroinflammation201613126410.1186/s12974‑016‑0738‑927724914
    [Google Scholar]
  67. GuadagnoJ. SwanP. ShaikhR. CreganS.P. Microglia-derived IL-1β triggers p53-mediated cell cycle arrest and apoptosis in neural precursor cells.Cell Death Dis.201566e177910.1038/cddis.2015.15126043079
    [Google Scholar]
  68. RosaJ.M. Farré-AlinsV. OrtegaM.C. NavarreteM. Lopez-RodriguezA.B. Palomino-AntolínA. Fernández-LópezE. Vila-del SolV. DecoutyC. Narros-FernándezP. ClementeD. EgeaJ. TLR4 pathway impairs synaptic number and cerebrovascular functions through astrocyte activation following traumatic brain injury.Br. J. Pharmacol.2021178173395341310.1111/bph.1548833830504
    [Google Scholar]
  69. JiangH. WangY. LiangX. XingX. XuX. ZhouC. Toll-like receptor 4 knockdown attenuates brain damage and neuroinflammation after traumatic brain injury via inhibiting neuronal autophagy and astrocyte activation.Cell. Mol. Neurobiol.20183851009101910.1007/s10571‑017‑0570‑529222622
    [Google Scholar]
  70. ChenX. WuS. ChenC. XieB. FangZ. HuW. ChenJ. FuH. HeH. Omega-3 polyunsaturated fatty acid supplementation attenuates microglial-induced inflammation by inhibiting the HMGB1/TLR4/NF-κB pathway following experimental traumatic brain injury.J. Neuroinflammation201714114310.1186/s12974‑017‑0917‑328738820
    [Google Scholar]
  71. ZhongL. XuY. ZhuoR. WangT. WangK. HuangR. WangD. GaoY. ZhuY. ShengX. ChenK. WangN. ZhuL. CanD. MartenY. ShinoharaM. LiuC.C. DuD. SunH. WenL. XuH. BuG. ChenX.F. Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer’s disease model.Nat. Commun.2019101136510.1038/s41467‑019‑09118‑930911003
    [Google Scholar]
  72. De RosaM. PaceU. RegaD. CostabileV. DuraturoF. IzzoP. DelrioP. Genetics, diagnosis and management of colorectal cancer (Review).Oncol. Rep.20153431087109610.3892/or.2015.410826151224
    [Google Scholar]
  73. SinghN. GuravA. SivaprakasamS. BradyE. PadiaR. ShiH. ThangarajuM. PrasadP.D. ManicassamyS. MunnD.H. LeeJ.R. OffermannsS. GanapathyV. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis.Immunity201440112813910.1016/j.immuni.2013.12.00724412617
    [Google Scholar]
  74. RooksM.G. GarrettW.S. Gut microbiota, metabolites and host immunity.Nat. Rev. Immunol.201616634135210.1038/nri.2016.4227231050
    [Google Scholar]
  75. LiR. ZhouR. WangH. LiW. PanM. YaoX. ZhanW. YangS. XuL. DingY. ZhaoL. Gut microbiota-stimulated cathepsin K secretion mediates TLR4-dependent M2 macrophage polarization and promotes tumor metastasis in colorectal cancer.Cell Death Differ.201926112447246310.1038/s41418‑019‑0312‑y30850734
    [Google Scholar]
  76. YuT. GuoF. YuY. SunT. MaD. HanJ. Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy.Cell20171703548563.e1610.1016/j.cell.2017.07.008
    [Google Scholar]
  77. SheyhidinI. NabiG. HasimA. ZhangR.P. AiniwaerJ. MaH. WangH. Overexpression of TLR3, TLR4, TLR7 and TLR9 in esophageal squamous cell carcinoma.World J. Gastroenterol.201117323745375110.3748/wjg.v17.i32.374521990957
    [Google Scholar]
  78. RousseauM.C. HsuR.Y.C. SpicerJ.D. McDonaldB. ChanC.H.F. PereraR.M. GianniasB. ChowS.C. RousseauS. LawS. FerriL.E. Lipopolysaccharide-induced toll-like receptor 4 signaling enhances the migratory ability of human esophageal cancer cells in a selectin-dependent manner.Surgery20131541697710.1016/j.surg.2013.03.00623809486
    [Google Scholar]
  79. SantarpiaL. LippmanS.M. El-NaggarA.K. Targeting the MAPK–RAS–RAF signaling pathway in cancer therapy.Expert Opin. Ther. Targets201216110311910.1517/14728222.2011.64580522239440
    [Google Scholar]
  80. WuK. YangY. LiuD. QiY. ZhangC. ZhaoJ. ZhaoS. Activation of PPARγ suppresses proliferation and induces apoptosis of esophageal cancer cells by inhibiting TLR4-dependent MAPK pathway.Oncotarget2016728445724458210.18632/oncotarget.1006727323819
    [Google Scholar]
  81. Fels ElliottD.R. PernerJ. LiX. SymmonsM.F. VerstakB. EldridgeM. BowerL. O’DonovanM. GayN.J. FitzgeraldR.C. Impact of mutations in Toll-like receptor pathway genes on esophageal carcinogenesis.PLoS Genet.2017135e100680810.1371/journal.pgen.100680828531216
    [Google Scholar]
  82. SekiE. De MinicisS. ÖsterreicherC.H. KluweJ. OsawaY. BrennerD.A. SchwabeR.F. TLR4 enhances TGF-β signaling and hepatic fibrosis.Nat. Med.200713111324133210.1038/nm166317952090
    [Google Scholar]
  83. DapitoD.H. MencinA. GwakG.Y. PradereJ.P. JangM.K. MederackeI. CavigliaJ.M. KhiabanianH. AdeyemiA. BatallerR. LefkowitchJ.H. BowerM. FriedmanR. SartorR.B. RabadanR. SchwabeR.F. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4.Cancer Cell201221450451610.1016/j.ccr.2012.02.00722516259
    [Google Scholar]
  84. SamuelM.S. LopezJ.I. McGheeE.J. CroftD.R. StrachanD. TimpsonP. MunroJ. SchröderE. ZhouJ. BruntonV.G. BarkerN. CleversH. SansomO.J. AndersonK.I. WeaverV.M. OlsonM.F. Actomyosin-mediated cellular tension drives increased tissue stiffness and β-catenin activation to induce epidermal hyperplasia and tumor growth.Cancer Cell201119677679110.1016/j.ccr.2011.05.00821665151
    [Google Scholar]
  85. LeventalK.R. YuH. KassL. LakinsJ.N. EgebladM. ErlerJ.T. FongS.F.T. CsiszarK. GiacciaA. WeningerW. YamauchiM. GasserD.L. WeaverV.M. Matrix crosslinking forces tumor progression by enhancing integrin signaling.Cell2009139589190610.1016/j.cell.2009.10.02719931152
    [Google Scholar]
  86. de VicenteL.G. PintoA.P. da RochaA.L. PauliJ.R. de MouraL.P. CintraD.E. RopelleE.R. da SilvaA.S.R. Role of TLR4 in physical exercise and cardiovascular diseases.Cytokine202013615527310.1016/j.cyto.2020.15527332932194
    [Google Scholar]
  87. DuffieldJ.S. ForbesS.J. ConstandinouC.M. ClayS. PartolinaM. VuthooriS. WuS. LangR. IredaleJ.P. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair.J. Clin. Invest.20051151566510.1172/JCI20052267515630444
    [Google Scholar]
  88. YangL.Y. LuoQ. LuL. ZhuW.W. SunH.T. WeiR. LinZ.F. WangX.Y. WangC.Q. LuM. JiaH.L. ChenJ.H. ZhangJ.B. QinL.X. Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response.J. Hematol. Oncol.2020131310.1186/s13045‑019‑0836‑031907001
    [Google Scholar]
  89. LuH. XuX. FuD. GuY. FanR. YiH. HeX. WangC. OuyangB. ZhaoP. WangL. XuP. ChengS. WangZ. ZouD. HanL. ZhaoW. Butyrate-producing Eubacterium rectale suppresses lymphomagenesis by alleviating the TNF-induced TLR4/MyD88/NF-κB axis.Cell Host Microbe202230811391150.e710.1016/j.chom.2022.07.00335952646
    [Google Scholar]
  90. WangL. ZhaoY. QianJ. SunL. LuY. LiH. LiY. YangJ. CaiZ. YiQ. Toll-like receptor-4 signaling in mantle cell lymphoma.Cancer2013119478279110.1002/cncr.2779222915070
    [Google Scholar]
  91. DueM.R. PiekarzA.D. WilsonN. FeldmanP. RipschM.S. ChavezS. YinH. KhannaR. WhiteF.A. Neuroexcitatory effects of morphine-3-glucuronide are dependent on Toll-like receptor 4 signaling.J. Neuroinflammation20129172510.1186/1742‑2094‑9‑20022898544
    [Google Scholar]
  92. WangH. HuangM. WangW. ZhangY. MaX. LuoL. XuX. XuL. ShiH. XuY. WangA. XuT. Microglial TLR4-induced TAK1 phosphorylation and NLRP3 activation mediates neuroinflammation and contributes to chronic morphine-induced antinociceptive tolerance.Pharmacol. Res.202116510548210.1016/j.phrs.2021.10548233549727
    [Google Scholar]
  93. LiuT. HanQ. ChenG. HuangY. ZhaoL.X. BertaT. GaoY.J. JiR.R. Toll-like receptor 4 contributes to chronic itch, alloknesis, and spinal astrocyte activation in male mice.Pain2016157480681710.1097/j.pain.000000000000043926645545
    [Google Scholar]
  94. AgalaveN.M. RudjitoR. FarinottiA.B. KhoonsariP.E. SandorK. NomuraY. Szabo-PardiT.A. UrbinaC.M. PaladaV. PriceT.J. Erlandsson HarrisH. BurtonM.D. KultimaK. SvenssonC.I. Sex-dependent role of microglia in disulfide high mobility group box 1 protein-mediated mechanical hypersensitivity.Pain2021162244645810.1097/j.pain.000000000000203332773600
    [Google Scholar]
  95. SorgeR.E. LaCroix-FralishM.L. TuttleA.H. SotocinalS.G. AustinJ.S. RitchieJ. ChandaM.L. GrahamA.C. TophamL. BeggsS. SalterM.W. MogilJ.S. Spinal cord Toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice.J. Neurosci.20113143154501545410.1523/JNEUROSCI.3859‑11.201122031891
    [Google Scholar]
  96. SuW. CuiH. WuD. YuJ. MaL. ZhangX. HuangY. MaC. Suppression of TLR4-MyD88 signaling pathway attenuated chronic mechanical pain in a rat model of endometriosis.J. Neuroinflammation20211816510.1186/s12974‑020‑02066‑y33673857
    [Google Scholar]
  97. AkiyamaT. CarstensM.I. IkomaA. CevikbasF. SteinhoffM. CarstensE. Mouse model of touch-evoked itch (alloknesis).J. Invest. Dermatol.201213271886189110.1038/jid.2012.5222418875
    [Google Scholar]
  98. ChenO. HeQ. HanQ. FurutaniK. GuY. OlexaM. JiR.R. Mechanisms and treatments of neuropathic itch in a mouse model of lymphoma.J. Clin. Invest.20231334e16080710.1172/JCI16080736520531
    [Google Scholar]
  99. O’NeillL.A.J. BryantC.E. DoyleS.L. Therapeutic targeting of Toll-like receptors for infectious and inflammatory diseases and cancer.Pharmacol. Rev.200961217719710.1124/pr.109.00107319474110
    [Google Scholar]
  100. NeumannE. LefèvreS. ZimmermannB. GayS. Müller-LadnerU. Rheumatoid arthritis progression mediated by activated synovial fibroblasts.Trends Mol. Med.2010161045846810.1016/j.molmed.2010.07.00420739221
    [Google Scholar]
  101. KowalskiM.L. WolskaA. GrzegorczykJ. HiltJ. JarzebskaM. DrobniewskiM. SynderM. KurowskiM. Increased responsiveness to toll-like receptor 4 stimulation in peripheral blood mononuclear cells from patients with recent onset rheumatoid arthritis.Mediators Inflamm.20082008113273210.1155/2008/13273218584044
    [Google Scholar]
  102. ChenY. SunW. GaoR. SuY. UmeharaH. DongL. GongF. The role of high mobility group box chromosomal protein 1 in Rheumatoid arthritis.Rheumatology (Oxford)201352101739174710.1093/rheumatology/ket13423584368
    [Google Scholar]
  103. CampoG.M. AvenosoA. D’AscolaA. PrestipinoV. ScuruchiM. NastasiG. CalatroniA. CampoS. Hyaluronan differently modulates TLR-4 and the inflammatory response in mouse chondrocytes.Biofactors2012381697610.1002/biof.20222287316
    [Google Scholar]
  104. BilalogluS. AphinyanaphongsY. JonesS. IturrateE. HochmanJ. BergerJ.S. Thrombosis in hospitalized patients with COVID-19 in a New York City Health System.JAMA2020324879980110.1001/jama.2020.1337232702090
    [Google Scholar]
  105. PiazzaG. CampiaU. HurwitzS. SnyderJ.E. RizzoS.M. PfefermanM.B. MorrisonR.B. LeivaO. FanikosJ. NauffalV. AlmarzooqZ. GoldhaberS.Z. Registry of arterial and venous thromboembolic complications in patients with COVID-19.J. Am. Coll. Cardiol.202076182060207210.1016/j.jacc.2020.08.07033121712
    [Google Scholar]
  106. BarrettT.J. LeeA.H. XiaY. LinL.H. BlackM. CotziaP. HochmanJ. BergerJ.S. Platelet and vascular biomarkers associate with thrombosis and death in coronavirus disease.Circ. Res.2020127794594710.1161/CIRCRESAHA.120.31780332757722
    [Google Scholar]
  107. BonaventuraA. VecchiéA. DagnaL. MartinodK. DixonD.L. Van TassellB.W. DentaliF. MontecuccoF. MassbergS. LeviM. AbbateA. Endothelial dysfunction and immunothrombosis as key pathogenic mechanisms in COVID-19.Nat. Rev. Immunol.202121531932910.1038/s41577‑021‑00536‑933824483
    [Google Scholar]
  108. MoweryN.T. TerzianW.T.H. NelsonA.C. Acute lung injury.Curr. Probl. Surg.202057510077710.1016/j.cpsurg.2020.10077732505224
    [Google Scholar]
  109. YangM. Acute lung injury in aortic dissection: New insights in anesthetic management strategies.J. Cardiothorac. Surg.202318114710.1186/s13019‑023‑02223‑337069575
    [Google Scholar]
  110. TakedaK. AkiraS. Toll-like receptors in innate immunity.Int. Immunol.200417111410.1093/intimm/dxh18615585605
    [Google Scholar]
  111. KimH.J. KimH. LeeJ.H. HwangboC. Toll-like receptor 4 (TLR4): New insight immune and aging.Immun. Ageing20232016710.1186/s12979‑023‑00383‑338001481
    [Google Scholar]
  112. PeriF. PiazzaM. Therapeutic targeting of innate immunity with Toll-like receptor 4 (TLR4) antagonists.Biotechnol. Adv.201230125126010.1016/j.biotechadv.2011.05.01421664961
    [Google Scholar]
  113. KawaiT. AkiraS. The role of pattern-recognition receptors in innate immunity: Update on Toll-like receptors.Nat. Immunol.201011537338410.1038/ni.186320404851
    [Google Scholar]
  114. DuanT. DuY. XingC. WangH.Y. WangR.F. Toll-like receptor Signaling and its role in cell-mediated immunity.Front. Immunol.20221381277410.3389/fimmu.2022.81277435309296
    [Google Scholar]
  115. LongM.E. MallampalliR.K. HorowitzJ.C. Pathogenesis of pneumonia and acute lung injury.Clin. Sci. (Lond.)20221361074776910.1042/CS2021087935621124
    [Google Scholar]
  116. World Health OrganizationClassification of atherosclerotic lesions.World Health Organ Tech Rep Ser.198557143120
    [Google Scholar]
  117. MoranA.E. ForouzanfarM.H. RothG.A. MensahG.A. EzzatiM. MurrayC.J.L. NaghaviM. Temporal trends in ischemic heart disease mortality in 21 world regions, 1980 to 2010: The Global Burden of Disease 2010 study.Circulation2014129141483149210.1161/CIRCULATIONAHA.113.00404224573352
    [Google Scholar]
  118. GimbroneM.A.Jr García-CardeñaG. Endothelial cell dysfunction and the pathobiology of atherosclerosis.Circ. Res.2016118462063610.1161/CIRCRESAHA.115.30630126892962
    [Google Scholar]
  119. CosteaP.I. HildebrandF. ArumugamM. BäckhedF. BlaserM.J. BushmanF.D. de VosW.M. EhrlichS.D. FraserC.M. HattoriM. HuttenhowerC. JefferyI.B. KnightsD. LewisJ.D. LeyR.E. OchmanH. O’TooleP.W. QuinceC. RelmanD.A. ShanahanF. SunagawaS. WangJ. WeinstockG.M. WuG.D. ZellerG. ZhaoL. RaesJ. KnightR. BorkP. Enterotypes in the landscape of gut microbial community composition.Nat. Microbiol.20173181610.1038/s41564‑017‑0072‑829255284
    [Google Scholar]
  120. WeiJ. ZhangY. LiH. WangF. YaoS. Toll-like receptor 4: A potential therapeutic target for multiple human diseases.Biomed. Pharmacother.2023166115338http://dx.doi.org/https://linkinghub.elsevier.com/retrieve/pii/S075333222301129010.1016/j.biopha.2023.11533837595428
    [Google Scholar]
  121. GaleazziM. BerteauM. SebbaA. BurmesterG.R. KvienT.K. MeaseP.J. FRI0118 Dekavil (F8IL10) – update on the results of clinical trials investigating the immunocytokine in patients with rheumatoid arthritis.Ann. Rheum. Dis.201877603604
    [Google Scholar]
  122. YeD LiuJ LiY ZhangX WangY HuX Clinical update related to the first-in-human trial of SYS6002 (CRB-701), a next-generation nectin-4 targeting antibody drug conjugate.J. Clin. Oncol.202442suppl_163151
    [Google Scholar]
  123. WessonW ZhouH KimS PatelM LewisN MartinT Characterizing clinical trials for CAR T targeting solid tumors from 2018 to 2023: A systematic review.J. Clin. Oncol.202442suppl_16e15080
    [Google Scholar]
  124. TanHN LamK RobertsJ SmithR TurnerA PatelH Adverse events of patients treated with antibody-drug conjugates in phase 1 clinical trials at the Royal Marsden Drug Development Unit from 2014 to 2024.J. Clin. Oncol.202442suppl_1e15020
    [Google Scholar]
  125. FarahnakK. BaiY.Z. YokoyamaY. MorkanD.B. LiuZ. AmruteJ.M. De Filippis FalconA. TeradaY. LiaoF. LiW. ShepherdH.M. HachemR.R. PuriV. LavineK.J. GelmanA.E. BharatA. KreiselD. NavaR.G. B cells mediate lung ischemia/reperfusion injury by recruiting classical monocytes via synergistic B cell receptor/TLR4 signaling.J. Clin. Invest.20241346e17011810.1172/JCI17011838488011
    [Google Scholar]
  126. KawaiT. AkiraS. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity.Immunity201134563765010.1016/j.immuni.2011.05.00621616434
    [Google Scholar]
  127. MantovaniA. AllavenaP. The interaction of the immune system with tumors: A new paradigm.Cancer Immunol. Immunother.20156411925432147
    [Google Scholar]
  128. BakerK.J. MatzingerP. The role of the immune system in cancer: A review.Cancer Immunol. Res.201643191197
    [Google Scholar]
  129. BuchananM.E. TzengS.C. The role of toll-like receptors in cancer: A review.Cancers (Basel)202012233832028617
    [Google Scholar]
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