The Role of Toll-Like Receptor 4 in Infectious and Noninfectious Inflammation

Toll-like receptor 4 (TLR4) belongs to the family of pattern recognition receptors (PRRs). They are highly conserved receptors that recognize conserved pathogen-associated molecular patterns (PAMPs), thus representing the first line of defense against infections. TLR4 has been long recognized as the sensing receptor for gram-negative lipopolysaccharide (LPS). In addition, it also binds endogenous molecules produced as a result of tissue injury. Hence, TLR4 represents a key receptor on which both infectious and noninfectious stimuli converge to induce a proinflammatory response. TLR4-mediated inflammation, triggered by exogenous or endogenous ligands, is also involved in several acute and chronic diseases, having a pivotal role as amplifier of the inflammatory response. This review focuses on the research progress about the role of TLR4 activation in infectious and noninfectious (e.g., sterile) inflammation and the effects of TLR4 signaling in some pathological conditions.

[1]  Juliet M. Taylor,et al.  The contribution of neuroinflammation to amyloid toxicity in Alzheimer's disease , 2016, Journal of neurochemistry.

[2]  Z. Jia,et al.  Calcineurin B stimulates cytokine production through a CD14-independent Toll-like receptor 4 pathway , 2015, Immunology and cell biology.

[3]  D. Hume,et al.  Dengue virus NS1 protein activates cells via Toll-like receptor 4 and disrupts endothelial cell monolayer integrity , 2015, Science Translational Medicine.

[4]  S. Vogel,et al.  CD14 dependence of TLR4 endocytosis and TRIF signaling displays ligand specificity and is dissociable in endotoxin tolerance , 2015, Proceedings of the National Academy of Sciences.

[5]  O. Garaschuk,et al.  Neuroinflammation in Alzheimer's disease , 2015, The Lancet Neurology.

[6]  Taro Kawai,et al.  Toll-Like Receptor Signaling Pathways , 2014, Front. Immunol..

[7]  T. Beißbarth,et al.  The regulatory toll-like receptor 4 genetic polymorphism rs11536889 is associated with renal, coagulation and hepatic organ failure in sepsis patients , 2014, Journal of Translational Medicine.

[8]  R. Hotchkiss,et al.  The new normal: immunomodulatory agents against sepsis immune suppression. , 2014, Trends in molecular medicine.

[9]  P. Angus,et al.  Role of toll‐like receptors in liver transplantation , 2014, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[10]  A. Vezzani Epilepsy and Inflammation in the Brain: Overview and Pathophysiology , 2014, Epilepsy currents.

[11]  J. Vincent,et al.  Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. , 2013, JAMA.

[12]  E. Hirsch,et al.  Toll like receptor 4 mediates cell death in a mouse MPTP model of Parkinson disease , 2013, Scientific Reports.

[13]  W. Poewe,et al.  Toll-like receptor 4 is required for α-synuclein dependent activation of microglia and astroglia , 2013, Glia.

[14]  Jean-Philippe Michaud,et al.  Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer’s disease-related pathology , 2013, Proceedings of the National Academy of Sciences.

[15]  G. Forloni,et al.  Neuroprotective Effects of Toll-Like Receptor 4 Antagonism in Spinal Cord Cultures and in a Mouse Model of Motor Neuron Degeneration , 2012, Molecular medicine.

[16]  T. V. van Gulik,et al.  The sterile immune response during hepatic ischemia/reperfusion. , 2012, Cytokine & growth factor reviews.

[17]  Y. Ogata,et al.  A Single Nucleotide Polymorphism in 3′-Untranslated Region Contributes to the Regulation of Toll-like Receptor 4 Translation* , 2012, The Journal of Biological Chemistry.

[18]  C. Wijmenga,et al.  Genetic variation in Toll-like receptors and disease susceptibility , 2012, Nature Immunology.

[19]  Koichi Fukase,et al.  Structural basis of species-specific endotoxin sensing by innate immune receptor TLR4/MD-2 , 2012, Proceedings of the National Academy of Sciences.

[20]  Annamaria Vezzani,et al.  High-mobility group box-1 impairs memory in mice through both toll-like receptor 4 and Receptor for Advanced Glycation End Products , 2011, Experimental Neurology.

[21]  F. Granucci,et al.  CD14 Controls the LPS-Induced Endocytosis of Toll-like Receptor 4 , 2011, Cell.

[22]  Jamaal A Rehman,et al.  TLR4 mutation reduces microglial activation, increases Aβ deposits and exacerbates cognitive deficits in a mouse model of Alzheimer's disease , 2011, Journal of Neuroinflammation.

[23]  W. Poewe,et al.  Toll-like receptor 4 promotes α-synuclein clearance and survival of nigral dopaminergic neurons. , 2011, The American journal of pathology.

[24]  T. Wan,et al.  Toll-like Receptor 4 (TLR4) Is Essential for Hsp70-like Protein 1 (HSP70L1) to Activate Dendritic Cells and Induce Th1 Response* , 2011, The Journal of Biological Chemistry.

[25]  J. Anink,et al.  Toll-like receptor signaling in amyotrophic lateral sclerosis spinal cord tissue , 2011, Neuroscience.

[26]  R. Kohman,et al.  The effects of age on lipopolysaccharide-induced cognitive deficits and interleukin-1β expression , 2011, Behavioural Brain Research.

[27]  L. O’Neill,et al.  MicroRNAs: the fine-tuners of Toll-like receptor signalling , 2011, Nature Reviews Immunology.

[28]  R. Bateman,et al.  Decreased Clearance of CNS β-Amyloid in Alzheimer’s Disease , 2010, Science.

[29]  Lian-tang Wang,et al.  Endogenous toll-like receptor ligands and their biological significance , 2010, Journal of cellular and molecular medicine.

[30]  S. Akira,et al.  A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release , 2010, Proceedings of the National Academy of Sciences.

[31]  C. Erridge Endogenous ligands of TLR2 and TLR4: agonists or assistants? , 2010, Journal of leukocyte biology.

[32]  M. Maze,et al.  The impact of IL-1 modulation on the development of lipopolysaccharide-induced cognitive dysfunction , 2010, Critical care.

[33]  E. Aronica,et al.  Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures , 2010, Nature Medicine.

[34]  K. Moore,et al.  CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer , 2009, Nature Immunology.

[35]  Kaleb M. Pauley,et al.  miR-146a Is Critical for Endotoxin-induced Tolerance , 2009, The Journal of Biological Chemistry.

[36]  M. Bokarewa,et al.  Resistin competes with lipopolysaccharide for binding to toll-like receptor 4 , 2009, Journal of cellular and molecular medicine.

[37]  M. Kashiwagi,et al.  Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease , 2009, Nature Medicine.

[38]  T. Billiar,et al.  Mechanisms of Toll-Like Receptor 4 (TLR4)-Mediated Inflammation After Cold Ischemia/Reperfusion in the Heart , 2009, Transplantation.

[39]  Hayyoung Lee,et al.  The structural basis of lipopolysaccharide recognition by the TLR4–MD-2 complex , 2009, Nature.

[40]  U. Müller,et al.  Differential regulation of toll-like receptor mRNAs in amyloid plaque-associated brain tissue of aged APP23 transgenic mice , 2009, Neuroscience Letters.

[41]  S. Akira,et al.  Protection from lethal Gram-negative bacterial sepsis by targeting Toll-like receptor 4 , 2009, Proceedings of the National Academy of Sciences.

[42]  M. Mattson,et al.  Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid β-peptide and the membrane lipid peroxidation product 4-hydroxynonenal , 2008, Experimental Neurology.

[43]  S. Hickman,et al.  Microglial Dysfunction and Defective β-Amyloid Clearance Pathways in Aging Alzheimer's Disease Mice , 2008, The Journal of Neuroscience.

[44]  B. Funke,et al.  High-Mobility Group Box-1 in Ischemia-Reperfusion Injury of the Heart , 2008, Circulation.

[45]  M. Netea,et al.  Functional Consequences of Toll-like Receptor 4 Polymorphisms , 2008, Molecular medicine.

[46]  Kai Zacharowski,et al.  The role of toll-like receptors , 2008 .

[47]  R. Nitsch,et al.  A Vicious Cycle Involving Release of Heat Shock Protein 60 from Injured Cells and Activation of Toll-Like Receptor 4 Mediates Neurodegeneration in the CNS , 2008, The Journal of Neuroscience.

[48]  G. Nicolardi,et al.  Expression of TLR4 and CD14 in the Central Nervous System (CNS) in a MPTP Mouse Model of Parkinson's-Like Disease , 2008, Immunopharmacology and immunotoxicology.

[49]  K. Yoshiura,et al.  Evidence for association between a Toll-like receptor 4 gene polymorphism and moderate/severe periodontitis in the Japanese population. , 2007, Journal of periodontal research.

[50]  T. Billiar,et al.  Toll-Like Receptor 4 Mediates the Early Inflammatory Response After Cold Ischemia/Reperfusion , 2007, Transplantation.

[51]  H. Wong,et al.  Hsp72 Induces Inflammation and Regulates Cytokine Production in Airway Epithelium through a TLR4- and NF-κB-Dependent Mechanism1 , 2007, The Journal of Immunology.

[52]  J. Kalbfleisch,et al.  Activation of Toll-like receptor 4 signaling contributes to hippocampal neuronal death following global cerebral ischemia/reperfusion , 2007, Journal of Neuroimmunology.

[53]  S. Chadban,et al.  TLR4 activation mediates kidney ischemia/reperfusion injury. , 2007, The Journal of clinical investigation.

[54]  Holger Heine,et al.  Role of the Toll-Like Receptor 4 in Neuroinflammation in Alzheimer’s Disease , 2007, Cellular Physiology and Biochemistry.

[55]  Hayyoung Lee,et al.  Crystal Structure of the TLR4-MD-2 Complex with Bound Endotoxin Antagonist Eritoran , 2007, Cell.

[56]  W. Nacken,et al.  Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock , 2007, Nature Medicine.

[57]  H. Ogawa,et al.  The extra domain A of fibronectin stimulates murine mast cells via Toll‐like receptor 4 , 2007, Journal of leukocyte biology.

[58]  O. Hurtado,et al.  Toll-Like Receptor 4 Is Involved in Brain Damage and Inflammation After Experimental Stroke , 2007, Circulation.

[59]  E. Verrier,et al.  Inhibition of Toll-like Receptor 4 With Eritoran Attenuates Myocardial Ischemia-Reperfusion Injury , 2006, Circulation.

[60]  M. Boukhvalova,et al.  Analysis of TLR4 Polymorphic Variants: New Insights into TLR4/MD-2/CD14 Stoichiometry, Structure, and Signaling1 , 2006, The Journal of Immunology.

[61]  F. Sallusto,et al.  A cyanobacterial LPS antagonist prevents endotoxin shock and blocks sustained TLR4 stimulation required for cytokine expression , 2006, The Journal of experimental medicine.

[62]  L. Joosten,et al.  Identification of Small Heat Shock Protein B8 (HSP22) as a Novel TLR4 Ligand and Potential Involvement in the Pathogenesis of Rheumatoid Arthritis1 , 2006, The Journal of Immunology.

[63]  T. Kielian Toll‐like receptors in central nervous system glial inflammation and homeostasis , 2006, Journal of neuroscience research.

[64]  G. Prestwich,et al.  Regulation of lung injury and repair by Toll-like receptors and hyaluronan , 2005, Nature Medicine.

[65]  Marian F Young,et al.  The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages. , 2005, The Journal of clinical investigation.

[66]  K. Tracey,et al.  The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion , 2005, The Journal of experimental medicine.

[67]  Kevin J. Tracey,et al.  High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal , 2005, Nature Reviews Immunology.

[68]  L. Romani Immunity to fungal infections , 2004, Nature Reviews Immunology.

[69]  S. Miller,et al.  Microglia Initiate Central Nervous System Innate and Adaptive Immune Responses through Multiple TLRs1 , 2004, The Journal of Immunology.

[70]  E. Verrier,et al.  Toll-like receptor 4 mediates ischemia/reperfusion injury of the heart. , 2004, The Journal of thoracic and cardiovascular surgery.

[71]  J. Simon,et al.  Hyaluronan Fragments Stimulate Endothelial Recognition of Injury through TLR4* , 2004, Journal of Biological Chemistry.

[72]  G. Pawelec Extrathymic T-cell differentiation in vitro , 2004, Nature Reviews Immunology.

[73]  J. Julien,et al.  Exacerbation of Motor Neuron Disease by Chronic Stimulation of Innate Immunity in a Mouse Model of Amyotrophic Lateral Sclerosis , 2004, The Journal of Neuroscience.

[74]  Shizuo Akira,et al.  Toll-like Receptor Signaling* , 2003, Journal of Biological Chemistry.

[75]  J. Oyama,et al.  Reduced Myocardial Ischemia-Reperfusion Injury in Toll-Like Receptor 4-Deficient Mice , 2003, Circulation.

[76]  L. Kwak,et al.  Toll-Like Receptor 4-Dependent Activation of Dendritic Cells by β-Defensin 2 , 2002, Science.

[77]  S. Akira,et al.  Involvement of Toll-like Receptor (TLR) 2 and TLR4 in Cell Activation by Mannuronic Acid Polymers* , 2002, The Journal of Biological Chemistry.

[78]  D. Golenbock,et al.  Cutting Edge: The Immunostimulatory Activity of the Lung Surfactant Protein-A Involves Toll-Like Receptor 41 , 2002, The Journal of Immunology.

[79]  S. Akira,et al.  Essential role of MD-2 in LPS responsiveness and TLR4 distribution , 2002, Nature Immunology.

[80]  Carsten J. Kirschning,et al.  The Endoplasmic Reticulum-resident Heat Shock Protein Gp96 Activates Dendritic Cells via the Toll-like Receptor 2/4 Pathway* , 2002, The Journal of Biological Chemistry.

[81]  J. Platt,et al.  Receptor-Mediated Monitoring of Tissue Well-Being Via Detection of Soluble Heparan Sulfate by Toll-Like Receptor 41 , 2002, The Journal of Immunology.

[82]  Y. Kawai,et al.  Toll-Like Receptor 4-MD-2 Complex Mediates the Signal Transduction Induced by Flavolipin, an Amino Acid-Containing Lipid Unique to Flavobacterium meningosepticum , 2002, The Journal of Immunology.

[83]  Michael Rehli,et al.  Novel Signal Transduction Pathway Utilized by Extracellular HSP70 , 2002, The Journal of Biological Chemistry.

[84]  T. Ahrens,et al.  Oligosaccharides of Hyaluronan Activate Dendritic Cells via Toll-like Receptor 4 , 2002, The Journal of experimental medicine.

[85]  P. Tobias,et al.  MD-2 binds to bacterial lipopolysaccharide. , 2001, Journal of endotoxin research.

[86]  W. Hancock,et al.  Fibrinogen Stimulates Macrophage Chemokine Secretion Through Toll-Like Receptor 41 , 2001, The Journal of Immunology.

[87]  D. Schwartz,et al.  Molecular Genetic Analysis of an Endotoxin Nonresponder Mutant Cell Line , 2001, The Journal of experimental medicine.

[88]  N. Qureshi,et al.  Diphosphoryl Lipid A from Rhodobacter sphaeroides Blocks the Binding and Internalization of Lipopolysaccharide in RAW 264.7 Cells1 , 2001, The Journal of Immunology.

[89]  K. Miyake,et al.  Micrococcus luteus Teichuronic Acids Activate Human and Murine Monocytic Cells in a CD14- and Toll-Like Receptor 4-Dependent Manner , 2001, Infection and Immunity.

[90]  Douglas T. Golenbock,et al.  Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus , 2000, Nature Immunology.

[91]  T. Yoshida,et al.  Mouse Toll-like Receptor 4·MD-2 Complex Mediates Lipopolysaccharide-mimetic Signal Transduction by Taxol* , 2000, The Journal of Biological Chemistry.

[92]  H. Kolb,et al.  Cutting Edge: Heat Shock Protein 60 Is a Putative Endogenous Ligand of the Toll-Like Receptor-4 Complex1 , 2000, The Journal of Immunology.

[93]  R. Medzhitov,et al.  Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium. , 1999, The Journal of clinical investigation.

[94]  Yoshinori Nagai,et al.  MD-2, a Molecule that Confers Lipopolysaccharide Responsiveness on Toll-like Receptor 4 , 1999, The Journal of experimental medicine.

[95]  S. Akira,et al.  Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. , 1999, Journal of immunology.

[96]  L. Larivière,et al.  Endotoxin-tolerant Mice Have Mutations in Toll-like Receptor 4 (Tlr4) , 1999, The Journal of experimental medicine.

[97]  P. Ricciardi-Castagnoli,et al.  Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. , 1998, Science.

[98]  C. Janeway,et al.  A human homologue of the Drosophila Toll protein signals activation of adaptive immunity , 1997, Nature.

[99]  J. Frelinger,et al.  Mouse genetic locus Lps influences susceptibility to Neisseria meningitidis infection , 1988, Infection and immunity.

[100]  R. Macdermott,et al.  Genetic control of susceptibility to Salmonella typhimurium in mice: role of the LPS gene. , 1980, Journal of immunology.

[101]  T. Billiar,et al.  Toll-like Receptor 4 (TLR4) Antagonist Eritoran Tetrasodium Attenuates Liver Ischemia and Reperfusion Injury through Inhibition of High-Mobility Group Box Protein B1 (HMGB1) Signaling , 2015, Molecular medicine.

[102]  H. Ischiropoulos,et al.  Molecular Neurodegeneration BioMed Central Review , 2009 .

[103]  H. Etlinger,et al.  the Journal of Immunology , 2006 .

[104]  L. Becker Myocardial Reperfusion Injury , 2004, Journal of Thrombosis and Thrombolysis.