1,316
Views
110
CrossRef citations to date
0
Altmetric
Review

Targeting toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders

, , , & ORCID Icon
Pages 865-882 | Received 16 Jul 2019, Accepted 01 Oct 2019, Published online: 20 Oct 2019

References

  • Dowling JK, Mansell A. Toll-like receptors: the swiss army knife of immunity and vaccine development. Clin Transl Immunol. 2016;5:e85.
  • Al-Ofi EA, Al-Ghamdi BS. High-mobility group box 1, an endogenous ligand of toll-like receptors 2 and 4, induces astroglial inflammation via nuclear factor kappa B pathway. Folia Morphol. 2019;78:10–16.
  • Wardill HR, Van Sebille YZA, Mander KA, et al. Toll-like receptor 4 signaling: a common biological mechanism of regimen-related toxicities: an emerging hypothesis for neuropathy and gastrointestinal toxicity. Cancer Treat Rev. 2015;41:122–128.
  • Molteni M, Gemma S, Rossetti C. The role of toll-like receptor 4 in infectious and noninfectious inflammation. Mediators Inflamm. 2016;2016:1–9.
  • Rahimifard M, Maqbool F, Moeini-Nodeh S, et al. Targeting the TLR4 signaling pathway by polyphenols: a novel therapeutic strategy for neuroinflammation. Ageing Res Rev. 2017;36:11–19.
  • Oblak A, Jerala R. The molecular mechanism of species-specific recognition of lipopolysaccharides by the MD-2/TLR4 receptor complex. Mol Immunol. 2015;63:134–142.
  • Bahrun U, Kimoto M, Tsukamoto H, et al. Preparation and characterization of agonistic monoclonal antibodies against toll-like receptor 4-MD-2 complex. Hybridoma. 2007;26:393–400.
  • Ohta S, Bahrun U, Shimazu R, et al. Induction of long-term lipopolysaccharide tolerance by an agonistic monoclonal antibody to the toll-like receptor 4/MD-2 complex. Clin Vaccine Immunol. 2006;13:1131–1136.
  • Rajaiah R, Perkins DJ, Ireland DDC, et al. CD14 dependence of TLR4 endocytosis and TRIF signaling displays ligand specificity and is dissociable in endotoxin tolerance. Proc Natl Acad Sci. 2015;112:8391–8396.
  • Fu R, Shen Q, Xu P, et al. Phagocytosis of microglia in the central nervous system diseases. Mol Neurobiol. 2014;49:1422–1434.
  • Esen N, Kielian T. Central role for MyD88 in the responses of microglia to pathogen-associated molecular patterns. J Immunol. 2014;176:6802–6811.
  • Zanoni I, Ostuni R, Marek LR, et al. CD14 controls the LPS-induced endocytosis of toll-like receptor 4. Cell. 2011;147:868–880.
  • Wang J, Kobayashi M, Han M, et al. MyD88 is involved in the signalling pathway for Taxol-induced apoptosis and TNF-alpha expression in human myelomonocytic cells. Br J Haematol. 2002;118:638–645.
  • Ruckdeschel K, Pfaffinger G, Haase R, et al. Signaling of apoptosis through TLRs critically involves toll/IL-1 receptor domain-containing adapter inducing IFN-β, but not MyD88, in bacteria-infected murine macrophages. J Immunol. 2004;173:3320–3328.
  • Qin H, Niyongere SA, Lee SJ, et al. Expression and functional significance of SOCS-1 and SOCS-3 in astrocytes. J Immunol. 2008;181:3167–3176.
  • Płóciennikowska A, Hromada-Judycka A, Borzęcka K, et al. Co-operation of TLR4 and raft proteins in LPS-induced pro-inflammatory signaling. Cell Mol Life Sci. 2015;72:557–581.
  • Vaure C, Liu Y. A comparative review of toll-like receptor 4 expression and functionality in different animal species. Front Immunol. 2014;5:1–15.
  • Uhlén M, Fagerberg L, Hallström BM, et al. Tissue-based map of the human proteome. Science. 2015;347:1260419.
  • Zschaler J, Schlorke D, Arnhold J. Differences in innate immune response between man and mouse. Crit Rev Immunol. 2014;34:433–454.
  • Schroder K, Irvine KM, Taylor MS, et al. Conservation and divergence in toll-like receptor 4-regulated gene expression in primary human versus mouse macrophages. Proc Natl Acad Sci. 2012;109:E944–E953.
  • Bsibsi M, Ravid R, Gveric D, et al. Broad expression of toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol. 2002;61:1013–1021.
  • Sankowski R, Mader S, Valdes-Ferrer SI. Systemic inflammation and the brain: novel roles of genetic, molecular, and environmental cues as drivers of neurodegeneration. Front Cell Neurosci. 2015;9:28.
  • Gambuzza M, Licata N, Palella E, et al. Targeting toll-like receptors: emerging therapeutics for multiple sclerosis management. J Neuroimmunol. 2011;239:1–12.
  • Buchanan MM, Hutchinson M, Watkins LR, et al. Toll-like receptor 4 in CNS pathologies. J Neurochem. 2010;114:13–27.
  • Chavarría C, Rodríguez-Bottero S, Quijano C, et al. Impact of monomeric, oligomeric and fibrillar alpha-synuclein on astrocyte reactivity and toxicity to neurons. Biochem J. 2018;475:3153–3169.
  • Rannikko EH, Weber SS, Kahle PJ. Exogenous α-synuclein induces toll-like receptor 4 dependent inflammatory responses in astrocytes. BMC Neurosci. 2015;16:57.
  • Walter S, Letiembre M, Liu Y, et al. Role of the toll-like receptor 4 in neuroinflammation in Alzheimer’s disease. Cell Physiol Biochem. 2007;20:947–956.
  • Land WG. The role of damage-associated molecular patterns in human diseases: part I - promoting inflammation and immunity. Sultan Qaboos Univ Med J. 2015;15:e9–e21.
  • Tahara K, Kim HD, Jin JJ, et al. Role of toll-like receptor signalling in Aβ uptake and clearance. Brain. 2006;129:3006–3019.
  • Qin Y, Liu Y, Hao W, et al. Stimulation of TLR4 attenuates Alzheimer’s disease–related symptoms and pathology in tau-transgenic mice. J Immunol. 2016;197:3281–3292.
  • Shen Y, Qin H, Chen J, et al. Postnatal activation of TLR4 in astrocytes promotes excitatory synaptogenesis in hippocampal neurons. J Cell Biol. 2016;215:719–734.
  • Gorina R, Font-Nieves M, Márquez-Kisinousky L, et al. Astrocyte TLR4 activation induces a proinflammatory environment through the interplay between MyD88-dependent NFκB signaling, MAPK, and Jak1/Stat1 pathways. Glia. 2011;59:242–255.
  • Henneberger C, Steinhäuser C. Astrocytic TLR4 at the crossroads of inflammation and seizure susceptibility. J Cell Biol. 2016;215:607–609.
  • Delgado M, Singh S, De Haro S, et al. Autophagy and pattern recognition receptors in innate immunity. Immunol Rev. 2009;227:189–202.
  • Aurelian L, Warnock KT, Balan I, et al. TLR4 signaling in VTA dopaminergic neurons regulates impulsivity through tyrosine hydroxylase modulation. Transl Psychiatry. 2016;6:e815.
  • Grasselli C, Ferrari D, Zalfa C, et al. Toll-like receptor 4 modulation influences human neural stem cell proliferation and differentiation. Cell Death Dis. 2018;9:280.
  • Yang Y, Han C, Guo L, et al. High expression of the HMGB1–TLR4 axis and its downstream signaling factors in patients with Parkinson’s disease and the relationship of pathological staging. Brain Behav. 2018;8:e00948.
  • Owens T. Toll-like receptors in neurodegeneration. Curr Top Microbiol Immunol. 2009;336:105–120.
  • Neher JJ, Neniskyte U, Zhao J-W, et al. Inhibition of microglial phagocytosis is sufficient to prevent inflammatory neuronal death. J Immunol. 2011;186:4973–4983.
  • Probert L. TNF and its receptors in the CNS: the essential, the desirable and the deleterious effects. Neuroscience. 2015;302:2–22.
  • Yao L, Kan EM, Lu J, et al. Toll-like receptor 4 mediates microglial activation and production of inflammatory mediators in neonatal rat brain following hypoxia: role of TLR4 in hypoxic microglia. J Neuroinflammation. 2013;10:785.
  • Madeira JM, Little JP, Klegeris A. Microglia secretome: from neurotoxins to neurotrophins. In: Kaur C, Ling EA, editors. Microglia: biology, Functions and Roles in Disease. New York: Nova Publishers; 2012. p. 73–92.
  • Hansen DV, Hanson JE, Sheng M. Microglia in Alzheimer’s disease. J Cell Biol. 2018;217:459–472.
  • Bramlett HM, Dietrich WD. Pathophysiology of cerebral ischemia and brain trauma: similarities and differences. J Cereb Blood Flow Metab. 2004;24:133–150.
  • Martínez-Valverde T, Sánchez-Guerrero A, Vidal-Jorge M, et al. Characterization of the ionic profile of the extracellular space of the injured and ischemic brain: a microdialysis study. J Neurotrauma. 2016;34:74–85.
  • Paudel YN, Shaikh MF, Chakraborti A, et al. HMGB1: A common biomarker and potential target for TBI, neuroinflammation, epilepsy, and cognitive dysfunction. Front Neurosci. 2018;12:628.
  • Jiang H, Wang Y, Liang X, et al. Toll-like receptor 4 knockdown attenuates brain damage and neuroinflammation after traumatic brain injury via inhibiting neuronal autophagy and astrocyte activation. Cell Mol Neurobiol. 2018;38:1009–1019.
  • Yang QW, Li JC, Lu FL, et al. Upregulated expression of toll-like receptor 4 in monocytes correlates with severity of acute cerebral infarction. J Cereb Blood Flow Metab. 2008;28:1588–1596.
  • Tang Y, Le W. Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol. 2016;53:1181–1194.
  • Calvo-Rodríguez M, de la Fuente C, García-Durillo M, et al. Aging and amyloid β oligomers enhance TLR4 expression, LPS-induced Ca2+ responses, and neuron cell death in cultured rat hippocampal neurons. J Neuroinflammation. 2017;14:24.
  • Fellner L, Irschick R, Schanda K, et al. Toll-like receptor 4 is required for α-synuclein dependent activation of microglia and astroglia. Glia. 2013;61:349–360.
  • Fletcher JM, Lalor SJ, Sweeney CM, et al. T cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Clin Exp Immunol. 2010;162:1–11.
  • Marta M, Andersson Å, Isaksson M, et al. Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis. Eur J Immunol. 2008;38:565–575.
  • Van Langelaar J, Van Der Vuurst De Vries RM, Janssen M, et al. T helper 17.1 cells associate with multiple sclerosis disease activity: perspectives for early intervention. Brain. 2018;141:1334–1349.
  • Bogie JFJ, Stinissen P, Hendriks JJA. Macrophage subsets and microglia in multiple sclerosis. Acta Neuropathol. 2014;128:191–213.
  • Marta M, Meier UC, Lobell A. Regulation of autoimmune encephalomyelitis by toll-like receptors. Autoimmun Rev. 2009;8:506–509.
  • Träger U, Andre R, Lahiri N, et al. HTT-lowering reverses Huntington’s disease immune dysfunction caused by NFκB pathway dysregulation. Brain. 2014;137:819–833.
  • Estrada Sánchez AM, Mejía-Toiber J, Massieu L. Excitotoxic neuronal death and the pathogenesis of Huntington’s disease. Arch Med Res. 2008;39:265–276.
  • Griffioen K, Mattson MP, Okun E. Deficiency of toll-like receptors 2, 3 or 4 extends life expectancy in Huntington’s disease mice. Heliyon. 2018;4:e00508.
  • Sofroniew MV. Astrogliosis. Cold Spring Harb Perspect Biol. 2015;7:a020420.
  • Patel AJ, Gray CW. Neurotrophic factors produced by astrocytes involved in the regulation of cholinergic neurons in the central nervous system. Biol Pathol Astrocyte-Neuron Interact. 2013;2:103–115.
  • Morizawa YM, Hirayama Y, Ohno N, et al. Reactive astrocytes function as phagocytes after brain ischemia via ABCA1-mediated pathway. Nat Commun. 2017;8:28.
  • Li Y, Zhang L, Kallakuri S, et al. Quantitative relationship between axonal injury and mechanical response in a rodent head impact acceleration model. J Neurotrauma. 2011;28:1767–1782.
  • Holley JE, Gveric D, Newcombe J, et al. Astrocyte characterization in the multiple sclerosis glial scar. Neuropathol Appl Neurobiol. 2003;29:434–444.
  • Dong XX, Wang Y, Qin ZH. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol Sin. 2009;30:379–387.
  • Zou J, Crews FT. Glutamate/NMDA excitotoxicity and HMGB1/TLR4 neuroimmune toxicity converge as components of neurodegeneration. AIMS Mol Sci. 2015;2:77–100.
  • Cui J, Yu S, Li Y, et al. Direct binding of toll-like receptor 4 to ionotropic glutamate receptor N-methyl-D-aspartate subunit 1 induced by lipopolysaccharide in microglial cells N9 and EOC 20. Int J Mol Med. 2018;41:1323–1330.
  • Butchbach MER, Tian G, Guo H, et al. Association of excitatory amino acid transporters, especially EAAT2, with cholesterol-rich lipid raft microdomains: importance for excitatory amino acid transporter localization and function. J Biol Chem. 2004;279:34388–34396.
  • Lubetzki C, Stankoff B. Demyelination in multiple sclerosis. Handb Clin Neurol. 2014;122:89–99.
  • Podbielska M, Banik NL, Kurowska E, et al. Myelin recovery in multiple sclerosis: the challenge of remyelination. Brain Sci. 2013;3:1282–1324.
  • Dulamea AO. Role of oligodendrocyte dysfunction in demyelination, remyelination and neurodegeneration in multiple sclerosis. Adv Exp Med Biol. 2017;958:91–127.
  • Skripuletz T, Miller E, Grote L, et al. Lipopolysaccharide delays demyelination and promotes oligodendrocyte precursor proliferation in the central nervous system. Brain Behav Immun. 2011;25:1592–1606.
  • Church JS, Kigerl KA, Lerch JK, et al. TLR4 deficiency impairs oligodendrocyte gformation in the injured spinal cord. J Neurosci. 2016;36:6352–6364.
  • Church JS, Milich LM, Lerch JK, et al. E6020, a synthetic TLR4 agonist, accelerates myelin debris clearance, Schwann cell infiltration, and remyelination in the rat spinal cord. Glia. 2017;65:883–899.
  • Cai Z, Xiao M. Oligodendrocytes and Alzheimer’s disease. Int J Neurosci. 2016;126:97–104.
  • Botelho RJ, Grinstein S. Phagocytosis. Curr Biol. 2011;21:R533–R538.
  • Parzych KR, Klionsky DJ. An overview of autophagy: morphology, mechanism, and regulation. Antioxid Redox Signal. 2013;20:460–473.
  • Gomez-Arboledas A, Davila JC, Sanchez-Mejias E, et al. Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer’s disease. Glia. 2018;66:637–653.
  • Rajbhandari L, Tegenge MA, Shrestha S, et al. Toll-like receptor 4 deficiency impairs microglial phagocytosis of degenerating axons. Glia. 2014;62:1982–1991.
  • He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009;43:67–93.
  • Takeuchi O, Akira S. TLR4 signaling: negative regulation by degradation. Blood. 2007;110:794.
  • Tang S-C, Lathia JD, Selvaraj PK, et al. Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid beta-peptide and the membrane lipid peroxidation product 4-hydroxynonenal. Exp Neurol. 2008;213:114–121.
  • Jung DY, Lee H, Jung B-Y, et al. TLR4, but not TLR2, signals autoregulatory apoptosis of cultured microglia: a critical role of IFN-β as a decision maker. J Immunol. 2005;174:6467–6476.
  • Veenith TV, Carter EL, Geeraerts T, et al. Pathophysiologic mechanisms of cerebral ischemia and diffusion hypoxia in traumatic brain injury. JAMA Neurol. 2016;73:542–550.
  • Washington PM, Morffy N, Parsadanian M, et al. Experimental traumatic brain injury induces rapid aggregation and oligomerization of amyloid-beta in an Alzheimer’s disease mouse model. J Neurotrauma. 2013;31:125–134.
  • Petrou M, Dwamena BA, Foerster BR, et al. Amyloid deposition in Parkinson’s disease and cognitive impairment: a systematic review. Mov Disord. 2015;30:928–935.
  • Kalaitzakis ME, Graeber MB, Gentleman SM, et al. Striatal β-amyloid deposition in Parkinson’s disease with dementia. J Neuropathol Exp Neurol. 2008;67:155–161.
  • Bhadbhade A, Cheng DW. Amyloid precursor protein processing in Alzheimer’s disease. Iran J Child Neurol. 2012;6:1–4.
  • Zheng Q, Huang T, Zhang L, et al. Dysregulation of ubiquitin-proteasome system in neurodegenerative diseases. Front Aging Neurosci. 2016;8:303.
  • Stefanova N, Fellner L, Reindl M, et al. Toll-like receptor 4 promotes α-synuclein clearance and survival of nigral dopaminergic neurons. Am J Pathol. 2011;179:954–963.
  • Mullin S, Schapira AHV. Pathogenic mechanisms of neurodegeneration in Parkinson disease. Neurol Clin. 2015;33:1–17.
  • Bourdenx M, Bezard E, Dehay B. Lysosomes and alpha-synuclein form a dangerous duet leading to neuronal cell death. Front Neuroanat. 2014;8:83.
  • Woerman AL, Kazmi SA, Patel S, et al. MSA prions exhibit remarkable stability and resistance to inactivation. Acta Neuropathol. 2018;135:49–63.
  • Beyer K, Domingo-Sàbat M, Ariza A. Molecular pathology of Lewy body diseases. Int J Mol Sci. 2009;10:724–745.
  • Wakabayashi K, Tanji K, Mori F, et al. The Lewy body in Parkinson’s disease: molecules implicated in the formation and degradation of α-synuclein aggregates. Neuropathology. 2007;27:494–506.
  • Iqbal K, Liu F, Gong CX, et al. Tau in Alzheimer disease and related tauopathies. Curr Alzheimer Res. 2010;7:656–664.
  • Gong CX, Iqbal K. Hyperphosphorylation of microtubule-associated protein tau: a promising therapeutic target for Alzheimer disease. Curr Med Chem. 2008;15:2321–2328.
  • Yan X, Uronen RL, Huttunen HJ. The interaction of α-synuclein and tau: a molecular conspiracy in neurodegeneration? Semin Cell Dev Biol. 2018;5:S1084–9521.
  • Tidswell M, Tillis W, Larosa SP, et al. Phase 2 trial of eritoran tetrasodium (E5564), a toll-like receptor 4 antagonist, in patients with severe sepsis. Crit Care Med. 2010;38:72–83.
  • Lucas K, Maes M. Role of the toll-like receptor (TLR) radical cycle in chronic inflammation: possible treatments targeting the TLR4 pathway. Mol Neurobiol. 2013;48:190–204.
  • Sugiyama K, Muroi M, Tanamoto K. A novel TLR4-binding peptide that inhibits LPS-induced activation of NF-κB and in vivo toxicity. Eur J Pharmacol. 2008;594:152–156.
  • Kawamoto T, Sha T, Ii M, et al. Selective inhibition of toll-like receptor 4 signaling by the small molecule TAK-242. Crit Care. 2006;10:P154–P154.
  • Shah N, Montes De Oca M, Jover-Cobos M, et al. Role of toll-like receptor 4 in mediating multiorgan dysfunction in mice with acetaminophen induced acute liver failure. Liver Transplant. 2013;19:751–761.
  • Fellner A, Barhum Y, Angel A, et al. Toll-Like receptor-4 inhibitor TAK-242 attenuates motor dysfunction and spinal cord pathology in an amyotrophic lateral sclerosis mouse model. Int J Mol Sci. 2017;18:1666.
  • Palmer C, Peri F, Neumann F, et al. The synthetic glycolipid-based TLR4 antagonist FP7 negatively regulates in vitro and in vivo haematopoietic and non-haematopoietic vascular TLR4 signalling. Innate Immun. 2018;24:411–421.
  • Perrin-Cocon L, Aublin-Gex A, Sestito SE, et al. TLR4 antagonist FP7 inhibits LPS-induced cytokine production and glycolytic reprogramming in dendritic cells, and protects mice from lethal influenza infection. Sci Rep. 2017;7:40791.
  • Fort MM, Mozaffarian A, Stöver AG, et al. A synthetic TLR4 antagonist has anti-inflammatory effects in two murine models of inflammatory bowel disease. J Immunol. 2005;174:6416–6423.
  • Oda M, Yamamoto H, Shibutani M, et al. Vizantin inhibits endotoxin-mediated immune responses via the TLR 4/MD-2 complex. J Immunol. 2014;193:4507–4514.
  • Yamamoto H, Oda M, Kanno M, et al. Chemical hybridization of vizantin and lipid A to generate a novel LPS antagonist. Chem Pharm Bull Pharm Bull. 2015;64:246–257.
  • Oda M, Kurosawa M, Yamamoto H, et al. Sulfated vizantin induces formation of macrophage extracellular traps. Microbiol Immunol. 2018;62:310–316.
  • Shirey KA, Lai W, Scott AJ, et al. The TLR4 antagonist eritoran protects mice from lethal influenza infection. Nature. 2013;497:498–502.
  • Lin M, Yiu WH, Li RX, et al. The TLR4 antagonist CRX-526 protects against advanced diabetic nephropathy. Kidney Int. 2013;83:887–900.
  • Cighetti R, Ciaramelli C, Sestito SE, et al. Modulation of CD14 and TLR4×MD-2 activities by a synthetic lipid A mimetic. ChemBioChem. 2014;15:250–258.
  • Cluff CW, Baldridge JR, Stöver AG, et al. Synthetic toll-like receptor 4 agonists stimulate innate resistance to infectious challenge. Infect Immun. 2005;73:3044–3052.
  • Han Y, Zhao T, Cheng X, et al. Cortical inflammation is increased in a DSS-induced colitis mouse model. Neurosci Bull. 2018;34:1058–1066.
  • Pan LF, Yu L, Wang LM, et al. The toll-like receptor 4 antagonist TAK-242 protects against chronic pancreatitis in rats. Mol Med Rep. 2017;16:3863–3868.
  • Matsunaga N, Tsuchimori N, Matsumoto T, et al. TAK-242 (resatorvid), a small-molecule inhibitor of toll-like receptor (TLR) 4 signaling, binds selectively to TLR4 and interferes with interactions between TLR4 and its adaptor molecules. Mol Pharmacol. 2011;79:34–41.
  • Gaikwad S, Agrawal-Rajput R. Lipopolysaccharide from Rhodobacter sphaeroides attenuates microglia-mediated inflammation and phagocytosis and directs regulatory T cell response. Int J Inflam. 2015;2015:1–13.
  • Thorgersen EB, Macagno A, Rossetti C, et al. Cyanobacterial LPS antagonist (CyP)-A novel and efficient inhibitor of Escherichia coli LPS-induced cytokine response in the pig. Mol Immunol. 2008;45:3553–3557.
  • Glass CK, Saijo K, Winner B, et al. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140:918–934.
  • De Paola M, Mariani A, Bigini P, et al. Neuroprotective effects of toll-like receptor 4 antagonism in spinal cord cultures and in a mouse model of motor neuron degeneration. Mol Med. 2012;18:971–981.
  • Lei C, Wu B, Cao T, et al. Brain recovery mediated by toll-like receptor 4 in rats after intracerebral hemorrhage. Brain Res. 2016;1632:1–8.
  • Pålsson-McDermott EM, O’Neill LAJ. Signal transduction by the lipopolysaccharide receptor, toll-like receptor-4. Immunology. 2004;113:153–162.
  • Morefield GL, Hawkins LD, Ishizaka ST, et al. Synthetic toll-like receptor 4 agonist enhances vaccine efficacy in an experimental model of toxic shock syndrome. Clin Vaccine Immunol. 2007;14:1499–1504.
  • Wang X, Quinn PJ. Lipopolysaccharide: biosynthetic pathway and structure modification. Prog Lipid Res. 2010;49:97–107.
  • Michaud J-P, Halle M, Lampron A, et al. Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer’s disease-related pathology. Proc Natl Acad Sci. 2013;110:1941–1946.
  • Lu YC, Yeh WC, Ohashi PS. LPS/TLR4 signal transduction pathway. Cytokine. 2008;42:145–151.
  • Petrovsky N, Aguilar JC. Vaccine adjuvants: current state and future trends. Immunol Cell Biol. 2004;82:488–496.
  • Hayashi T, Crain B, Yao S, et al. Novel synthetic toll-like receptor 4/MD2 ligands attenuate sterile inflammation. J Pharmacol Exp Ther. 2014;350:330–340.
  • Neve JE, Wijesekera HP, Duffy S, et al. Euodenine A: a small-molecule agonist of human TLR4. J Med Chem. 2014;57:1252–1275.
  • Niu X, Yu Y, Guo H, et al. Molecular modeling reveals the inhibition mechanism and binding mode of ursolic acid to TLR4-MD2. Comput Theor Chem. 2018;1123:73–78.
  • Goff PH, Hayashi T, Martínez-Gil L, et al. Synthetic toll-like receptor 4 (TLR4) and TLR7 ligands as influenza virus vaccine adjuvants induce rapid, sustained, and broadly protective responses. J Virol. 2015;89:3221–3235.
  • Hawkins LD. A novel class of endotoxin receptor agonists with simplified structure, toll-like receptor 4-dependent immunostimulatory action, and adjuvant activity. J Pharmacol Exp Ther. 2003;300:655–661.
  • Przetak M, Chow J, Cheng H, et al. Novel synthetic LPS receptor agonists boost systemic and mucosal antibody responses in mice. Vaccine. 2003;21:961–970.
  • Tanaka A, Nakamura S, Seki M, et al. Toll-like receptor 4 agonistic antibody promotes innate immunity against severe pneumonia induced by coinfection with influenza virus and Streptococcus pneumoniae. Clin Vaccine Immunol. 2013;20:977–985.
  • Mata-Haro V, Cekic C, Martin M, et al. The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4. Science. 2007;316:1628–1632.
  • Ishizaka ST, Hawkins LD. E6020: a synthetic toll-like receptor 4 agonist as a vaccine adjuvant. Expert Rev Vaccines. 2007;6:773–784.
  • Rego Â, Viana SD, Ribeiro CAF, et al. Monophosphoryl lipid A: a promising tool for Alzheimer’s disease toll. J Alzheimer’s Dis. 2016;52:1189–1202.
  • Nakamura S, Iwanaga N, Seki M, et al. Toll-like receptor 4 agonistic antibody promotes host defense against chronic pseudomonas aeruginosa lung infection in mice. Infect Immun. 2016;84:1986–1993.
  • Tsukamoto H, Fukudome K, Takao S, et al. Reduced surface expression of TLR4 by a V254I point mutation accounts for the low lipopolysaccharide responder phenotype of BALB/c B cells. J Immunol. 2013;190:195–204.
  • Russell R, Brightling CE. Anti-IL-5 for severe asthma: aiming high to achieve success. Chest. 2016;150:766–768.
  • Rosenzweig HL, Lessov NS, Henshall DC, et al. Endotoxin preconditioning prevents cellular inflammatory response during ischemic neuroprotection in mice. Stroke. 2004;35:2576–2581.
  • Broad A, Jones D, Kirby J. Toll-like receptor (TLR) response tolerance: a key physiological “damage limitation” effect and an important potential opportunity for therapy. Curr Med Chem. 2006;13:2487–2502.
  • Liu H, Xin L, Chan BPL, et al. Interferon-β administration confers a beneficial outcome in a rabbit model of thromboembolic cerebral ischemia. Neurosci Lett. 2002;327:146–148.
  • Marsh B, Stevens SL, Packard AEB, et al. Systemic lipopolysaccharide protects the brain from ischemic injury by reprogramming the response of the brain to stroke: a critical role for IRF3. J Neurosci. 2009;29:9839–9849.
  • Pourbadie HG, Sayyah M, Khoshkholgh-Sima B, et al. Early minor stimulation of microglial TLR2 and TLR4 receptors attenuates Alzheimer’s disease–related cognitive deficit in rats: behavioral, molecular, and electrophysiological evidence. Neurobiol Aging. 2018;70:203–216.
  • Hosseini SM, Gholami Pourbadie H, Sayyah M, et al. Neuroprotective effect of monophosphoryl lipid A, a detoxified lipid A derivative, in photothrombotic model of unilateral selective hippocampal ischemia in rat. Behav Brain Res. 2018;347:26–36.
  • Deleu D. Rivastigmine in the treatment of Alzheimer’s disease. Eur Neurol. 2001;46:110.
  • Okun E, Griffioen KJ, Gen Son T, et al. TLR2 activation inhibits embryonic neural progenitor cell proliferation. J Neurochem. 2010;114:462–474.
  • Suzuki Y, Hattori K, Hamanaka J, et al. Pharmacological inhibition of TLR4-NOX4 signal protects against neuronal death in transient focal ischemia. Sci Rep. 2012;2:896.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.