Skip to main content
SpringerLink
Log in

Toll-like receptors: promising therapeutic targets for inflammatory diseases

  • Review
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

The health of living organisms is constantly challenged by bacterial and viral threats. The recognition of pathogenic microorganisms by diverse receptors triggers a variety of host defense mechanisms, leading to their eradication. Toll-like receptors (TLRs), which are type I transmembrane proteins, recognize specific signatures of the invading microbes and activate a cascade of downstream signals inducing the secretion of inflammatory cytokines, chemokines, and type I interferons. The TLR response not only counteracts the pathogens but also initiates and shapes the adaptive immune response. Under normal conditions, inflammation is downregulated after the removal of the pathogen and cellular debris. However, a dysfunctional TLR-mediated response maintains a chronic inflammatory state and leads to local and systemic deleterious effects in host cells and tissues. Such inappropriate TLR response has been attributed to the development and progression of multiple diseases such as cancer, autoimmune, and inflammatory diseases. In this review, we discuss the emerging role of TLRs in the pathogenesis of inflammatory diseases and how targeting of TLRs offers a promising therapeutic strategy for the prevention and treatment of various inflammatory diseases. Additionally, we highlight a number of TLR-targeting agents that are in the developmental stage or in clinical trials.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Abdollahi-Roodsaz S, Joosten LA, Helsen MM, Walgreen B, Van Lent PL, Van Den Bersselaar LA, Koenders MI, Van Den Berg WB (2008) Shift from toll-like receptor 2 (TLR-2) toward TLR-4 dependency in the erosive stage of chronic streptococcal cell wall arthritis coincident with TLR-4-mediated interleukin-17 production. Arthritis Rheum 58:3753–3764

    Article  CAS  PubMed  Google Scholar 

  • Akira S, Hoshino K (2003) Myeloid differentiation factor 88-dependent and -independent pathways in toll-like receptor signaling. J Infect Dis 187(Suppl 2):S356–S363

    Article  CAS  PubMed  Google Scholar 

  • Alzabin S, Kong P, Medghalchi M, Palfreeman A, Williams R, Sacre S (2012) Investigation of the role of endosomal toll-like receptors in murine collagen-induced arthritis reveals a potential role for TLR7 in disease maintenance. Arthritis Res Ther 14:R142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anwar MA, Basith S, Choi S (2013) Negative regulatory approaches to the attenuation of toll-like receptor signaling. Exp Mol Med 45:e11

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Arslan F, De Kleijn DP, Timmers L, Doevendans PA, Pasterkamp G (2008) Bridging innate immunity and myocardial ischemia/reperfusion injury: the search for therapeutic targets. Curr Pharm Des 14:1205–1216

    Article  CAS  PubMed  Google Scholar 

  • Arslan F, Houtgraaf JH, Keogh B, Kazemi K, De Jong R, Mccormack WJ, O’neill LA, Mcguirk P, Timmers L, Smeets MB, Akeroyd L, Reilly M, Pasterkamp G, De Kleijn DP (2012) Treatment with OPN-305, a humanized anti-toll-Like receptor-2 antibody, reduces myocardial ischemia/reperfusion injury in pigs. Circ Cardiovasc Interv 5:279–287

    Article  CAS  PubMed  Google Scholar 

  • Balistreri CR, Candore G, Mirabile M, Lio D, Caimi G, Incalcaterra E, Caruso M, Hoffmann E, Caruso C (2008) TLR2 and age-related diseases: potential effects of Arg753Gln and Arg677Trp polymorphisms in acute myocardial infarction. Rejuvenation Res 11:293–296

    Article  CAS  PubMed  Google Scholar 

  • Baral P, Utaisincharoen P (2013) Sterile-α- and armadillo motif-containing protein inhibits the TRIF-dependent downregulation of signal regulatory protein α to interfere with intracellular bacterial elimination in Burkholderia pseudomallei-infected mouse macrophages. Infect Immun 81:3463–3471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Basith S, Manavalan B, Lee G, Kim SG, Choi S (2011) Toll-like receptor modulators: a patent review (2006–2010). Expert Opin Ther Pat 21:927–944

    Article  CAS  PubMed  Google Scholar 

  • Batsford S, Dunn J, Mihatsch M (2011) Induction of experimental arthritis by borrelial lipoprotein and CpG motifs: are toll-like receptors 2, 4, 9 or CD-14 involved? Open Rheumatol J 5:18–23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bezemer GF, Sagar S, Van Bergenhenegouwen J, Georgiou NA, Garssen J, Kraneveld AD, Folkerts G (2012) Dual role of toll-like receptors in asthma and chronic obstructive pulmonary disease. Pharmacol Rev 64:337–358

    Article  CAS  PubMed  Google Scholar 

  • Bhinder G, Stahl M, Sham HP, Crowley SM, Morampudi V, Dalwadi U, Ma C, Jacobson K, Vallance BA (2014) Intestinal epithelium-specific MyD88 signaling impacts host susceptibility to infectious colitis by promoting protective goblet cell and antimicrobial responses. Infect Immun 82:3753–3763

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bianchi ME (2007) DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 81:1–5

    Article  CAS  PubMed  Google Scholar 

  • Bielinski SJ, Hall JL, Pankow JS, Boerwinkle E, Matijevic-Aleksic N, He M, Chambless L, Folsom AR (2011) Genetic variants in TLR2 and TLR4 are associated with markers of monocyte activation: the atherosclerosis risk in communities MRI study. Hum Genet 129:655–662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blasius AL, Beutler B (2010) Intracellular toll-like receptors. Immunity 32:305–315

    Article  CAS  PubMed  Google Scholar 

  • Boone DL, Turer EE, Lee EG, Ahmad RC, Wheeler MT, Tsui C, Hurley P, Chien M, Chai S, Hitotsumatsu O, Mcnally E, Pickart C, Ma A (2004) The ubiquitin-modifying enzyme A20 is required for termination of toll-like receptor responses. Nat Immunol 5:1052–1060

    Article  CAS  PubMed  Google Scholar 

  • Brint EK, Xu D, Liu H, Dunne A, Mckenzie AN, O’neill LA, Liew FY (2004) ST2 is an inhibitor of interleukin 1 receptor and toll-like receptor 4 signaling and maintains endotoxin tolerance. Nat Immunol 5:373–379

    Article  CAS  PubMed  Google Scholar 

  • Brown J, Wang H, Hajishengallis GN, Martin M (2011) TLR-signaling networks: an integration of adaptor molecules, kinases, and cross-talk. J Dent Res 90:417–427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Celhar T, Fairhurst AM (2014) Toll-like receptors in systemic lupus erythematosus: potential for personalized treatment. Front Pharmacol 5:265

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chen JQ, Szodoray P, Zeher M (2016) Toll-like receptor pathways in autoimmune diseases. Clin Rev Allergy Immunol 50:1–17

    Article  CAS  PubMed  Google Scholar 

  • Cighetti R, Ciaramelli C, Sestito SE, Zanoni I, Kubik L, Arda-Freire A, Calabrese V, Granucci F, Jerala R, Martin-Santamaria S, Jimenez-Barbero J, Peri F (2014) Modulation of CD14 and TLR4.MD-2 activities by a synthetic lipid A mimetic. ChemBioChem 15:250–258

    Article  CAS  PubMed  Google Scholar 

  • Clancy RM, Markham AJ, Buyon JP (2016) Endosomal toll-like receptors in clinically overt and silent autoimmunity. Immunol Rev 269:76–84

    Article  CAS  PubMed  Google Scholar 

  • Cook DN, Pisetsky DS, Schwartz DA (2004) Toll-like receptors in the pathogenesis of human disease. Nat Immunol 5:975–979

    Article  CAS  PubMed  Google Scholar 

  • Cooke GS, Segal S, Hill AV, Tuberculosis G, Environment Study G, Oxford Pneumococcal Surveillance Study G (2002) Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med 347:1978–1980

    Article  PubMed  Google Scholar 

  • Cosmi L, Liotta F, Maggi E, Romagnani S, Annunziato F (2011) Th17 cells: new players in asthma pathogenesis. Allergy 66:989–998

    Article  CAS  PubMed  Google Scholar 

  • Curry JL, Qin JZ, Bonish B, Carrick R, Bacon P, Panella J, Robinson J, Nickoloff BJ (2003) Innate immune-related receptors in normal and psoriatic skin. Arch Pathol Lab Med 127:178–186

    CAS  PubMed  Google Scholar 

  • Davis ML, Levan TD, Yu F, Sayles H, Sokolove J, Robinson W, Michaud K, Thiele GM, Mikuls TR (2015) Associations of toll-like receptor (TLR)-4 single nucleotide polymorphisms and rheumatoid arthritis disease progression: an observational cohort study. Int Immunopharmacol 24:346–352

    Article  CAS  PubMed  Google Scholar 

  • De Nardo D (2015) Toll-like receptors: activation, signalling and transcriptional modulation. Cytokine 74:181–189

    Article  PubMed  CAS  Google Scholar 

  • Depaolo RW, Tang F, Kim I, Han M, Levin N, Ciletti N, Lin A, Anderson D, Schneewind O, Jabri B (2008) Toll-like receptor 6 drives differentiation of tolerogenic dendritic cells and contributes to LcrV-mediated plague pathogenesis. Cell Host Microbe 4:350–361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Depaolo RW, Kamdar K, Khakpour S, Sugiura Y, Wang W, Jabri B (2012) A specific role for TLR1 in protective T(H)17 immunity during mucosal infection. J Exp Med 209:1437–1444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Derkow K, Bauer JM, Hecker M, Paap BK, Thamilarasan M, Koczan D, Schott E, Deuschle K, Bellmann-Strobl J, Paul F, Zettl UK, Ruprecht K, Lehnardt S (2013) Multiple sclerosis: modulation of toll-like receptor (TLR) expression by interferon-beta includes upregulation of TLR7 in plasmacytoid dendritic cells. PLoS One 8:e70626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Diebold SS, Kaisho T, Hemmi H, Akira S, E Sousa CR (2004) Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303:1529–1531

    Article  CAS  PubMed  Google Scholar 

  • Divanovic S, Trompette A, Atabani SF, Madan R, Golenbock DT, Visintin A, Finberg RW, Tarakhovsky A, Vogel SN, Belkaid Y, Kurt-Jones EA, Karp CL (2005) Negative regulation of toll-like receptor 4 signaling by the toll-like receptor homolog RP105. Nat Immunol 6:571–578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Elson G, Page T, Buatois V, Daubeuf B, Chatel L, Cons L, Lippens C, Salgado-Pires S, Ferlin W, Kosco-Vilbois M, Midwood K, Shang L (2011) NI-0101, a therapeutic TLR 4 monoclonal antibody for rheumatoid arthritis. Arthritis Rheum 63:977

    Google Scholar 

  • Fagone P, Muthumani K, Mangano K, Magro G, Meroni PL, Kim JJ, Sardesai NY, Weiner DB, Nicoletti F (2014) VGX-1027 modulates genes involved in lipopolysaccharide-induced toll-like receptor 4 activation and in a murine model of systemic lupus erythematosus. Immunology 142:594–602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Farkas A, Tonel G, Nestle FO (2008) Interferon-alpha and viral triggers promote functional maturation of human monocyte-derived dendritic cells. Br J Dermatol 158:921–929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Flutter B, Nestle FO (2013) TLRs to cytokines: mechanistic insights from the imiquimod mouse model of psoriasis. Eur J Immunol 43:3138–3146

    Article  CAS  PubMed  Google Scholar 

  • Franchimont D, Vermeire S, El Housni H, Pierik M, Van Steen K, Gustot T, Quertinmont E, Abramowicz M, Van Gossum A, Deviere J, Rutgeerts P (2004) Deficient host-bacteria interactions in inflammatory bowel disease? The toll-like receptor (TLR)-4 Asp299gly polymorphism is associated with Crohn’s disease and ulcerative colitis. Gut 53:987–992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frolova L, Drastich P, Rossmann P, Klimesova K, Tlaskalova-Hogenova H (2008) Expression of toll-like receptor 2 (TLR2), TLR4, and CD14 in biopsy samples of patients with inflammatory bowel diseases: upregulated expression of TLR2 in terminal ileum of patients with ulcerative colitis. J Histochem Cytochem 56:267–274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frosali S, Pagliari D, Gambassi G, Landolfi R, Pandolfi F, Cianci R (2015) How the intricate interaction among toll-like receptors, microbiota, and intestinal immunity can influence gastrointestinal pathology. J Immunol Res 2015:489821

    Article  PubMed  PubMed Central  Google Scholar 

  • Fukata M, Michelsen KS, Eri R, Thomas LS, Hu B, Lukasek K, Nast CC, Lechago J, Xu R, Naiki Y, Soliman A, Arditi M, Abreu MT (2005) Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis. Am J Physiol Gastrointest Liver Physiol 288:G1055–G1065

    Article  CAS  PubMed  Google Scholar 

  • Furuta T, Kikuchi T, Akira S, Watanabe N, Yoshikawa Y (2006) Roles of the small intestine for induction of toll-like receptor 4-mediated innate resistance in naturally acquired murine toxoplasmosis. Int Immunol 18:1655–1662

    Article  CAS  PubMed  Google Scholar 

  • Gaspari AA (2006) Innate and adaptive immunity and the pathophysiology of psoriasis. J Am Acad Dermatol 54:S67–S80

    Article  PubMed  Google Scholar 

  • Gay NJ, Symmons MF, Gangloff M, Bryant CE (2014) Assembly and localization of toll-like receptor signalling complexes. Nat Rev Immunol 14:546–558

    Article  CAS  PubMed  Google Scholar 

  • Gearing AJ (2007) Targeting toll-like receptors for drug development: a summary of commercial approaches. Immunol Cell Biol 85:490–494

    Article  CAS  PubMed  Google Scholar 

  • Geremia A, Biancheri P, Allan P, Corazza GR, Di Sabatino A (2014) Innate and adaptive immunity in inflammatory bowel disease. Autoimmun Rev 13:3–10

    Article  CAS  PubMed  Google Scholar 

  • Gilliet M, Conrad C, Geiges M, Cozzio A, Thurlimann W, Burg G, Nestle FO, Dummer R (2004) Psoriasis triggered by toll-like receptor 7 agonist imiquimod in the presence of dermal plasmacytoid dendritic cell precursors. Arch Dermatol 140:1490–1495

    Article  CAS  PubMed  Google Scholar 

  • Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010) Mechanisms underlying inflammation in neurodegeneration. Cell 140:918–934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goh FG, Midwood KS (2012) Intrinsic danger: activation of toll-like receptors in rheumatoid arthritis. Rheumatology 51:7–23

    Article  CAS  PubMed  Google Scholar 

  • Guiducci C, Gong M, Xu Z, Gill M, Chaussabel D, Meeker T, Chan JH, Wright T, Punaro M, Bolland S, Soumelis V, Banchereau J, Coffman RL, Pascual V, Barrat FJ (2010) TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus. Nature 465:937–941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hammad H, Chieppa M, Perros F, Willart MA, Germain RN, Lambrecht BN (2009) House dust mite allergen induces asthma via toll-like receptor 4 triggering of airway structural cells. Nat Med 15:410–416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han C, Jin J, Xu S, Liu H, Li N, Cao X (2010) Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b. Nat Immunol 11:734–742

    Article  CAS  PubMed  Google Scholar 

  • Hari A, Flach TL, Shi Y, Mydlarski PR (2010) Toll-like receptors: role in dermatological disease. Mediat Inflamm 2010:437246

    Article  CAS  Google Scholar 

  • He Z, Shotorbani SS, Jiao Z, Su Z, Tong J, Liu Y, Shen P, Ma J, Gao J, Wang T, Xia S, Shao Q, Wang S, Xu H (2012) HMGB1 promotes the differentiation of Th17 via up-regulating TLR2 and IL-23 of CD14+ monocytes from patients with rheumatoid arthritis. Scand J Immunol 76:483–490

    Article  CAS  PubMed  Google Scholar 

  • Heimesaat MM, Fischer A, Siegmund B, Kupz A, Niebergall J, Fuchs D, Jahn HK, Freudenberg M, Loddenkemper C, Batra A, Lehr HA, Liesenfeld O, Blaut M, Gobel UB, Schumann RR, Bereswill S (2007) Shift towards pro-inflammatory intestinal bacteria aggravates acute murine colitis via toll-like receptors 2 and 4. PLoS One 2:e662

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Heneka MT, Golenbock DT, Latz E (2015) Innate immunity in Alzheimer’s disease. Nat Immunol 16:229–236

    Article  CAS  PubMed  Google Scholar 

  • Herman S, Fischer A, Pfatschbacher J, Hoffmann M, Steiner G (2011) A TLR 9 antagonist diminishes arthritis severity in a rat model of rheumatoid arthritis. Ann Rheum Dis 70:A39

    Google Scholar 

  • Hoffjan S, Stemmler S, Parwez Q, Petrasch-Parwez E, Arinir U, Rohde G, Reinitz-Rademacher K, Schultze-Werninghaus G, Bufe A, Epplen JT (2005) Evaluation of the toll-like receptor 6 Ser249Pro polymorphism in patients with asthma, atopic dermatitis and chronic obstructive pulmonary disease. BMC Med Genet 6:34

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Holtzman MJ, Byers DE, Alexander-Brett J, Wang X (2014) The role of airway epithelial cells and innate immune cells in chronic respiratory disease. Nat Rev Immunol 14:686–698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang QQ, Sobkoviak R, Jockheck-Clark AR, Shi B, Mandelin AM 2nd, Tak PP, Haines GK 3rd, Nicchitta CV, Pope RM (2009) Heat shock protein 96 is elevated in rheumatoid arthritis and activates macrophages primarily via TLR2 signaling. J Immunol 182:4965–4973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iwahashi M, Yamamura M, Aita T, Okamoto A, Ueno A, Ogawa N, Akashi S, Miyake K, Godowski PJ, Makino H (2004) Expression of toll-like receptor 2 on CD16+ blood monocytes and synovial tissue macrophages in rheumatoid arthritis. Arthritis Rheum 50:1457–1467

    Article  CAS  PubMed  Google Scholar 

  • Janeway CA Jr, Medzhitov R (1998) Introduction: the role of innate immunity in the adaptive immune response. Semin Immunol 10:349–350

    Article  PubMed  Google Scholar 

  • Jiang A, Zhu F, Tang J, Kandimalla ER, La Monica N, Agrawal S (2012) IMO-8400, a novel TLR7, TLR8 and TLR9 antagonist, inhibits disease development in mouse models of psoriasis (119.8). J Immunol Res 188(119):8

    Google Scholar 

  • Jin MS, Lee JO (2008) Structures of the toll-like receptor family and its ligand complexes. Immunity 29:182–191

    Article  CAS  PubMed  Google Scholar 

  • Jin JJ, Kim HD, Maxwell JA, Li L, Fukuchi K (2008) Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer’s disease. J Neuroinflamm 5:23

    Article  CAS  Google Scholar 

  • Joosten LA, Koenders MI, Smeets RL, Heuvelmans-Jacobs M, Helsen MM, Takeda K, Akira S, Lubberts E, Van De Loo FA, Van Den Berg WB (2003) Toll-like receptor 2 pathway drives streptococcal cell wall-induced joint inflammation: critical role of myeloid differentiation factor 88. J Immunol 171:6145–6153

    Article  CAS  PubMed  Google Scholar 

  • Kandimalla ER, Bhagat L, Wang D, Yu D, Sullivan T, La Monica N, Agrawal S (2013) Design, synthesis and biological evaluation of novel antagonist compounds of toll-like receptors 7, 8 and 9. Nucleic Acids Res 41:3947–3961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kawai T, Akira S (2005) Toll-like receptor downstream signaling. Arthritis Res Ther 7:12–19

    Article  CAS  PubMed  Google Scholar 

  • Kawai T, Akira S (2007) TLR signaling. Semin Immunol 19:24–32

    Article  CAS  PubMed  Google Scholar 

  • Kawai T, Akira S (2010) The role of pattern-recognition receptors in innate immunity: update on toll-like receptors. Nat Immunol 11:373–384

    Article  CAS  PubMed  Google Scholar 

  • Kawasaki T, Kawai T (2014) Toll-like receptor signaling pathways. Front Immunol 5:461

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kayagaki N, Phung Q, Chan S, Chaudhari R, Quan C, O’rourke KM, Eby M, Pietras E, Cheng G, Bazan JF, Zhang Z, Arnott D, Dixit VM (2007) DUBA: a deubiquitinase that regulates type I interferon production. Science 318:1628–1632

    Article  CAS  PubMed  Google Scholar 

  • Keogh B, Parker AE (2011) Toll-like receptors as targets for immune disorders. Trends Pharmacol Sci 32:435–442

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi K, Hernandez LD, Galan JE, Janeway CA Jr, Medzhitov R, Flavell RA (2002) IRAK-M is a negative regulator of toll-like receptor signaling. Cell 110:191–202

    Article  CAS  PubMed  Google Scholar 

  • Kormann MS, Depner M, Hartl D, Klopp N, Illig T, Adamski J, Vogelberg C, Weiland SK, Von Mutius E, Kabesch M (2008) Toll-like receptor heterodimer variants protect from childhood asthma. J Allergy Clin Immunol 122:86–92

    Article  CAS  PubMed  Google Scholar 

  • Kumar H, Kawai T, Akira S (2011) Pathogen recognition by the innate immune system. Int Rev Immunol 30:16–34

    Article  CAS  PubMed  Google Scholar 

  • Lamphier M, Zheng W, Latz E, Spyvee M, Hansen H, Rose J, Genest M, Yang H, Shaffer C, Zhao Y, Shen Y, Liu C, Liu D, Mempel TR, Rowbottom C, Chow J, Twine NC, Yu M, Gusovsky F, Ishizaka ST (2014) Novel small molecule inhibitors of TLR7 and TLR9: mechanism of action and efficacy in vivo. Mol Pharmacol 85:429–440

    Article  PubMed  CAS  Google Scholar 

  • Landreth GE, Reed-Geaghan EG (2009) Toll-like receptors in Alzheimer’s disease. Curr Top Microbiol Immunol 336:137–153

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lebre MC, Antons JC, Kalinski P, Schuitemaker JH, Van Capel TM, Kapsenberg ML, De Jong EC (2003) Double-stranded RNA-exposed human keratinocytes promote Th1 responses by inducing a Type-1 polarized phenotype in dendritic cells: role of keratinocyte-derived tumor necrosis factor alpha, type I interferons, and interleukin-18. J Invest Dermatol 120:990–997

    Article  CAS  PubMed  Google Scholar 

  • Lee PY, Kumagai Y, Li Y, Takeuchi O, Yoshida H, Weinstein J, Kellner ES, Nacionales D, Barker T, Kelly-Scumpia K, Van Rooijen N, Kumar H, Kawai T, Satoh M, Akira S, Reeves WH (2008) TLR7-dependent and FcgammaR-independent production of type I interferon in experimental mouse lupus. J Exp Med 205:2995–3006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee Y, Kim H, Kim S, Kim KH, Chung JH (2010) Activation of toll-like receptors 2, 3 or 5 induces matrix metalloproteinase-1 and -9 expression with the involvement of MAPKs and NF-kappaB in human epidermal keratinocytes. Exp Dermatol 19:e44–e49

    Article  PubMed  Google Scholar 

  • Lee CC, Avalos AM, Ploegh HL (2012) Accessory molecules for toll-like receptors and their function. Nat Rev Immunol 12:168–179

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lee YH, Choi SJ, Ji JD, Song GG (2016) Association between toll-like receptor polymorphisms and systemic lupus erythematosus: a meta-analysis update. Lupus 25:593–601

    Article  CAS  PubMed  Google Scholar 

  • Lehmann SM, Kruger C, Park B, Derkow K, Rosenberger K, Baumgart J, Trimbuch T, Eom G, Hinz M, Kaul D, Habbel P, Kalin R, Franzoni E, Rybak A, Nguyen D, Veh R, Ninnemann O, Peters O, Nitsch R, Heppner FL, Golenbock D, Schott E, Ploegh HL, Wulczyn FG, Lehnardt S (2012) An unconventional role for miRNA: let-7 activates toll-like receptor 7 and causes neurodegeneration. Nat Neurosci 15:827–835

    Article  CAS  PubMed  Google Scholar 

  • Lehnardt S, Wennekamp J, Freyer D, Liedtke C, Krueger C, Nitsch R, Bechmann I, Weber JR, Henneke P (2007) TLR2 and caspase-8 are essential for group B Streptococcus-induced apoptosis in microglia. J Immunol 179:6134–6143

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Cao H, Wang N, Xiang Y, Lu Y, Zhao K, Zheng J, Zhou H (2011) A novel antagonist of TLR9 blocking all classes of immunostimulatory CpG-ODNs. Vaccine 29:2193–2198

    Article  CAS  PubMed  Google Scholar 

  • Liew FY, Xu D, Brint EK, O’neill LA (2005) Negative regulation of toll-like receptor-mediated immune responses. Nat Rev Immunol 5:446–458

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Buckley JM, Redmond HP, Wang JH (2010) ST2 negatively regulates TLR2 signaling, but is not required for bacterial lipoprotein-induced tolerance. J Immunol 184:5802–5808

    Article  CAS  PubMed  Google Scholar 

  • Lu Z, Zhang X, Li Y, Lopes-Virella MF, Huang Y (2015) TLR4 antagonist attenuates atherogenesis in LDL receptor-deficient mice with diet-induced type 2 diabetes. Immunobiology 220:1246–1254

    Article  CAS  PubMed  Google Scholar 

  • Lun SW, Wong CK, Ko FW, Hui DS, Lam CW (2009) Expression and functional analysis of toll-like receptors of peripheral blood cells in asthmatic patients: implication for immunopathological mechanism in asthma. J Clin Immunol 29:330–342

    Article  CAS  PubMed  Google Scholar 

  • Ma C, Ma Z, Fu Q, Ma S (2013) Curcumin attenuates allergic airway inflammation by regulation of CD4+ CD25+ regulatory T cells (Tregs)/Th17 balance in ovalbumin-sensitized mice. Fitoterapia 87:57–64

    Article  CAS  PubMed  Google Scholar 

  • Mansell A, Smith R, Doyle SL, Gray P, Fenner JE, Crack PJ, Nicholson SE, Hilton DJ, O’neill LA, Hertzog PJ (2006) Suppressor of cytokine signaling 1 negatively regulates toll-like receptor signaling by mediating Mal degradation. Nat Immunol 7:148–155

    Article  CAS  PubMed  Google Scholar 

  • Matsunaga N, Tsuchimori N, Matsumoto T, Ii M (2011) 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 79:34–41

    Article  CAS  PubMed  Google Scholar 

  • Mcinnes IB, O’dell JR (2010) State-of-the-art: rheumatoid arthritis. Ann Rheum Dis 69:1898–1906

    Article  CAS  PubMed  Google Scholar 

  • Mcinturff JE, Modlin RL, Kim J (2005) The role of toll-like receptors in the pathogenesis and treatment of dermatological disease. J Investig Dermatol 125:1–8

    Article  CAS  PubMed  Google Scholar 

  • Medzhitov R (2007) Recognition of microorganisms and activation of the immune response. Nature 449:819–826

    Article  CAS  PubMed  Google Scholar 

  • Meng L, Zhu W, Jiang C, He X, Hou W, Zheng F, Holmdahl R, Lu S (2010) Toll-like receptor 3 upregulation in macrophages participates in the initiation and maintenance of pristane-induced arthritis in rats. Arthritis Res Ther 12:R103

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Meylan E, Tschopp J (2008) IRAK2 takes its place in TLR signaling. Nat Immunol 9:581–582

    Article  CAS  PubMed  Google Scholar 

  • Miller LS, Sorensen OE, Liu PT, Jalian HR, Eshtiaghpour D, Behmanesh BE, Chung W, Starner TD, Kim J, Sieling PA, Ganz T, Modlin RL (2005) TGF-alpha regulates TLR expression and function on epidermal keratinocytes. J Immunol 174:6137–6143

    Article  CAS  PubMed  Google Scholar 

  • Millien VO, Lu W, Shaw J, Yuan X, Mak G, Roberts L, Song LZ, Knight JM, Creighton CJ, Luong A, Kheradmand F, Corry DB (2013) Cleavage of fibrinogen by proteinases elicits allergic responses through toll-like receptor 4. Science 341:792–796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miranda-Hernandez S, Gerlach N, Fletcher JM, Biros E, Mack M, Korner H, Baxter AG (2011) Role for MyD88, TLR2 and TLR9 but not TLR1, TLR4 or TLR6 in experimental autoimmune encephalomyelitis. J Immunol 187:791–804

    Article  CAS  PubMed  Google Scholar 

  • Mistry P, Laird MH, Schwarz RS, Greene S, Dyson T, Snyder GA, Xiao TS, Chauhan J, Fletcher S, Toshchakov VY, Mackerell AD Jr, Vogel SN (2015) Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain. Proc Natl Acad Sci USA 112:5455–5460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Montes AH, Asensi V, Alvarez V, Valle E, Ocana MG, Meana A, Carton JA, Paz J, Fierer J, Celada A (2006) The toll-like receptor 4 (Asp299Gly) polymorphism is a risk factor for Gram-negative and haematogenous osteomyelitis. Clin Exp Immunol 143:404–413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moon SJ, Park MK, Oh HJ, Lee SY, Kwok SK, Cho ML, Ju JH, Park KS, Kim HY, Park SH (2010) Engagement of toll-like receptor 3 induces vascular endothelial growth factor and interleukin-8 in human rheumatoid synovial fibroblasts. Korean J Intern Med 25:429–435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mudaliar H, Pollock C, Komala MG, Chadban S, Wu H, Panchapakesan U (2013) The role of toll-like receptor proteins (TLR) 2 and 4 in mediating inflammation in proximal tubules. Am J Physiol Renal Physiol 305:F143–F154

    Article  CAS  PubMed  Google Scholar 

  • Mullarkey M, Rose JR, Bristol J, Kawata T, Kimura A, Kobayashi S, Przetak M, Chow J, Gusovsky F, Christ WJ, Rossignol DP (2003) Inhibition of endotoxin response by e5564, a novel toll-like receptor 4-directed endotoxin antagonist. J Pharmacol Exp Ther 304:1093–1102

    Article  CAS  PubMed  Google Scholar 

  • Murad S (2014) Toll-like receptor 4 in inflammation and angiogenesis: a double-edged sword. Front Immunol 5:313

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nestle FO, Di Meglio P, Qin JZ, Nickoloff BJ (2009) Skin immune sentinels in health and disease. Nat Rev Immunol 9:679–691

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nickerson KM, Christensen SR, Shupe J, Kashgarian M, Kim D, Elkon K, Shlomchik MJ (2010) TLR9 regulates TLR7- and MyD88-dependent autoantibody production and disease in a murine model of lupus. J Immunol 184:1840–1848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nundel K, Green NM, Shaffer AL, Moody KL, Busto P, Eilat D, Miyake K, Oropallo MA, Cancro MP, Marshak-Rothstein A (2015) Cell-intrinsic expression of TLR9 in autoreactive B cells constrains BCR/TLR7-dependent responses. J Immunol 194:2504–2512

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • O’neill LA, Bryant CE, Doyle SL (2009) Therapeutic targeting of toll-like receptors for infectious and inflammatory diseases and cancer. Pharmacol Rev 61:177–197

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Opal SM, Laterre PF, Francois B, Larosa SP, Angus DC, Mira JP, Wittebole X, Dugernier T, Dugernier D, Tidswell M, Jauregui L, Krell K, Pachl J, Takahashi T, Peckelsen C, Cordasco E, Chang CS, Oeyen S, Aikawa N, Maruyama T, Schein R, Kalil AC, Van Nuffelen M, Lynn M, Rossignol DP, Gogate J, Roberts MB, Wheeler JL, Vincent JL, Vincent AS (2013) Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA 309:1154–1162

    Article  CAS  PubMed  Google Scholar 

  • Ospelt C, Gay S (2010) TLRs and chronic inflammation. Int J Biochem Cell Biol 42:495–505

    Article  CAS  PubMed  Google Scholar 

  • Ospelt C, Brentano F, Rengel Y, Stanczyk J, Kolling C, Tak PP, Gay RE, Gay S, Kyburz D (2008) Overexpression of toll-like receptors 3 and 4 in synovial tissue from patients with early rheumatoid arthritis: toll-like receptor expression in early and longstanding arthritis. Arthritis Rheum 58:3684–3692

    Article  CAS  PubMed  Google Scholar 

  • Palsson-Mcdermott EM, Doyle SL, Mcgettrick AF, Hardy M, Husebye H, Banahan K, Gong M, Golenbock D, Espevik T, O’neill LA (2009) TAG, a splice variant of the adaptor TRAM, negatively regulates the adaptor MyD88-independent TLR4 pathway. Nat Immunol 10:579–586

    Article  CAS  PubMed  Google Scholar 

  • Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, Ishizaka A, Abraham E (2004) Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 279:7370–7377

    Article  CAS  PubMed  Google Scholar 

  • Perkins DJ, Vogel SN (2016) Inflammation: species-specific TLR signalling—insight into human disease. Nat Rev Rheumatol 12:198–200

    Article  CAS  PubMed  Google Scholar 

  • Piazza M, Calabrese V, Damore G, Cighetti R, Gioannini T, Weiss J, Peri F (2012) A synthetic lipid A mimetic modulates human TLR4 activity. ChemMedChem 7:213–217

    Article  CAS  PubMed  Google Scholar 

  • Piccinini AM, Midwood KS (2010) DAMPening inflammation by modulating TLR signalling. Mediators Inflamm 2010:672395

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pierer M, Wagner U, Rossol M, Ibrahim S (2011) Toll-like receptor 4 is involved in inflammatory and joint destructive pathways in collagen-induced arthritis in DBA1 J mice. PLoS One 6:e23539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Prehaud C, Megret F, Lafage M, Lafon M (2005) Virus infection switches TLR-3-positive human neurons to become strong producers of beta interferon. J Virol 79:12893–12904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qian C, Cao X (2013) Regulation of toll-like receptor signaling pathways in innate immune responses. Ann N Y Acad Sci 1283:67–74

    Article  CAS  PubMed  Google Scholar 

  • Radstake TR, Roelofs MF, Jenniskens YM, Oppers-Walgreen B, Van Riel PL, Barrera P, Joosten LA, Van Den Berg WB (2004) Expression of toll-like receptors 2 and 4 in rheumatoid synovial tissue and regulation by proinflammatory cytokines interleukin-12 and interleukin-18 via interferon-gamma. Arthritis Rheum 50:3856–3865

    Article  CAS  PubMed  Google Scholar 

  • Ramani V, Madhusoodhanan R, Kosanke S, Awasthi S (2013) A TLR4-interacting SPA4 peptide inhibits LPS-induced lung inflammation. Innate Immun 19:596–610

    Article  PubMed  CAS  Google Scholar 

  • Renn CN, Sanchez DJ, Ochoa MT, Legaspi AJ, Oh CK, Liu PT, Krutzik SR, Sieling PA, Cheng G, Modlin RL (2006) TLR activation of Langerhans cell-like dendritic cells triggers an antiviral immune response. J Immunol 177:298–305

    Article  CAS  PubMed  Google Scholar 

  • Roelofs MF, Joosten LA, Abdollahi-Roodsaz S, Van Lieshout AW, Sprong T, Van Den Hoogen FH, Van Den Berg WB, Radstake TR (2005) The expression of toll-like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll-like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells. Arthritis Rheum 52:2313–2322

    Article  CAS  PubMed  Google Scholar 

  • Roelofs MF, Boelens WC, Joosten LA, Abdollahi-Roodsaz S, Geurts J, Wunderink LU, Schreurs BW, Van Den Berg WB, Radstake TR (2006) Identification of small heat shock protein B8 (HSP22) as a novel TLR4 ligand and potential involvement in the pathogenesis of rheumatoid arthritis. J Immunol 176:7021–7027

    Article  CAS  PubMed  Google Scholar 

  • Rose WA 2nd, Sakamoto K, Leifer CA (2012) TLR9 is important for protection against intestinal damage and for intestinal repair. Sci Rep 2:574

    PubMed  Google Scholar 

  • Rothlin CV, Ghosh S, Zuniga EI, Oldstone MBA, Lemke G (2007) TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 131:1124–1136

    Article  CAS  PubMed  Google Scholar 

  • Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, Gage FH, Glass CK (2009) A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137:47–59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saitoh T, Tun-Kyi A, Ryo A, Yamamoto M, Finn G, Fujita T, Akira S, Yamamoto N, Lu KP, Yamaoka S (2006) Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1. Nat Immunol 7:598–605

    Article  CAS  PubMed  Google Scholar 

  • Schnare M, Barton GM, Holt AC, Takeda K, Akira S, Medzhitov R (2001) Toll-like receptors control activation of adaptive immune responses. Nat Immunol 2:947–950

    Article  CAS  PubMed  Google Scholar 

  • Senhaji N, Diakite B, Serbati N, Zaid Y, Badre W, Nadifi S (2014) Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms: new data and a meta-analysis. BMC Gastroenterol 14:206

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Seung NR, Park EJ, Kim CW, Kim KH, Kim KJ, Cho HJ, Park HR (2007) Comparison of expression of heat-shock protein 60, toll-like receptors 2 and 4, and T-cell receptor gammadelta in plaque and guttate psoriasis. J Cutan Pathol 34:903–911

    Article  PubMed  Google Scholar 

  • Sham HP, Yu EYS, Gulen MF, Bhinder G, Stahl M, Chan JM, Brewster L, Morampudi V, Gibson DL, Hughes MR, Mcnagny KM, Li X, Vallance BA (2013) SIGIRR, a negative regulator of TLR/IL-1R signalling promotes microbiota dependent resistance to colonization by enteric bacterial pathogens. PLoS Pathog 9:e1003539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shannon J, Ernst P, Yamauchi Y, Olivenstein R, Lemiere C, Foley S, Cicora L, Ludwig M, Hamid Q, Martin JG (2008) Differences in airway cytokine profile in severe asthma compared to moderate asthma. Chest 133:420–426

    Article  CAS  PubMed  Google Scholar 

  • Shirey KA, Lai W, Scott AJ, Lipsky M, Mistry P, Pletneva LM, Karp CL, Mcalees J, Gioannini TL, Weiss J, Chen WH, Ernst RK, Rossignol DP, Gusovsky F, Blanco JC, Vogel SN (2013) The TLR4 antagonist Eritoran protects mice from lethal influenza infection. Nature 497:498–502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shmuel-Galia L, Aychek T, Fink A, Porat Z, Zarmi B, Bernshtein B, Brenner O, Jung S, Shai Y (2016) Neutralization of pro-inflammatory monocytes by targeting TLR2 dimerization ameliorates colitis. EMBO J 35:685–698

    Article  CAS  PubMed  Google Scholar 

  • Shotorbani SS, Su ZL, Xu HX (2011) Toll-like receptors are potential therapeutic targets in rheumatoid arthritis. World J Biol Chem 2:167–172

    Article  PubMed  PubMed Central  Google Scholar 

  • Sioud M (2010) Development of TLR7/8 small RNA antagonists. Methods Mol Biol 629:387–394

    PubMed  Google Scholar 

  • Sorensen LK, Havemose-Poulsen A, Sonder SU, Bendtzen K, Holmstrup P (2008) Blood cell gene expression profiling in subjects with aggressive periodontitis and chronic arthritis. J Periodontol 79:477–485

    Article  PubMed  CAS  Google Scholar 

  • Spiller S, Elson G, Ferstl R, Dreher S, Mueller T, Freudenberg M, Daubeuf B, Wagner H, Kirschning CJ (2008) TLR4-induced IFN-gamma production increases TLR2 sensitivity and drives Gram-negative sepsis in mice. J Exp Med 205:1747–1754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stewart CR, Stuart LM, Wilkinson K, Van Gils JM, Deng J, Halle A, Rayner KJ, Boyer L, Zhong R, Frazier WA, Lacy-Hulbert A, El Khoury J, Golenbock DT, Moore KJ (2010) CD36 ligands promote sterile inflammation through assembly of a toll-like receptor 4 and 6 heterodimer. Nat Immunol 11:155–161

    Article  CAS  PubMed  Google Scholar 

  • Streit WJ (2002) Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 40:133–139

    Article  PubMed  Google Scholar 

  • Suarez-Farinas M, Arbeit R, Jiang W, Ortenzio FS, Sullivan T, Krueger JG (2013) Suppression of molecular inflammatory pathways by toll-like receptor 7, 8, and 9 antagonists in a model of IL-23-induced skin inflammation. PLoS One 8:e84634

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Subramanian M, Thorp E, Hansson GK, Tabas I (2013) Treg-mediated suppression of atherosclerosis requires MYD88 signaling in DCs. J Clin Investig 123:179–188

    Article  CAS  PubMed  Google Scholar 

  • Suzuki M, Hisamatsu T, Podolsky DK (2003) Gamma interferon augments the intracellular pathway for lipopolysaccharide (LPS) recognition in human intestinal epithelial cells through coordinated up-regulation of LPS uptake and expression of the intracellular toll-like receptor 4-MD-2 complex. Infect Immun 71:3503–3511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tan Y, Zou KF, Qian W, Chen S, Hou XH (2014) Expression and implication of toll-like receptors TLR2, TLR4 and TLR9 in colonic mucosa of patients with ulcerative colitis. J Huazhong Univ Sci Technol Med Sci 34:785–790

    Article  CAS  PubMed  Google Scholar 

  • Tanaka J, Watanabe N, Kido M, Saga K, Akamatsu T, Nishio A, Chiba T (2009) Human TSLP and TLR3 ligands promote differentiation of Th17 cells with a central memory phenotype under Th2-polarizing conditions. Clin Exp Allergy 39:89–100

    Article  CAS  PubMed  Google Scholar 

  • Tang SC, Lathia JD, Selvaraj PK, Jo DG, Mughal MR, Cheng A, Siler DA, Markesbery WR, Arumugam TV, Mattson MP (2008) Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid beta-peptide and the membrane lipid peroxidation product 4-hydroxynonenal. Exp Neurol 213:114–121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taniguchi N, Kawahara K, Yone K, Hashiguchi T, Yamakuchi M, Goto M, Inoue K, Yamada S, Ijiri K, Matsunaga S, Nakajima T, Komiya S, Maruyama I (2003) High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine. Arthritis Rheum 48:971–981

    Article  CAS  PubMed  Google Scholar 

  • Tantisira K, Klimecki WT, Lazarus R, Palmer LJ, Raby BA, Kwiatkowski DJ, Silverman E, Vercelli D, Martinez FD, Weiss ST (2004) Toll-like receptor 6 gene (TLR6): single-nucleotide polymorphism frequencies and preliminary association with the diagnosis of asthma. Genes Immun 5:343–346

    Article  CAS  PubMed  Google Scholar 

  • Termeer C, Benedix F, Sleeman J, Fieber C, Voith U, Ahrens T, Miyake K, Freudenberg M, Galanos C, Simon JC (2002) Oligosaccharides of Hyaluronan activate dendritic cells via toll-like receptor 4. J Exp Med 195:99–111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tesmer LA, Lundy SK, Sarkar S, Fox DA (2008) Th17 cells in human disease. Immunol Rev 223:87–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thwaites R, Chamberlain G, Sacre S (2014) Emerging role of endosomal toll-like receptors in rheumatoid arthritis. Front Immunol 5:1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tirumurugaan KG, Dhanasekaran S, Raj GD, Raja A, Kumanan K, Ramaswamy V (2010) Differential expression of toll-like receptor mRNA in selected tissues of goat (Capra hircus). Vet Immunol Immunopathol 133:296–301

    Article  CAS  PubMed  Google Scholar 

  • Trompette A, Divanovic S, Visintin A, Blanchard C, Hegde RS, Madan R, Thorne PS, Wills-Karp M, Gioannini TL, Weiss JP, Karp CL (2009) Allergenicity resulting from functional mimicry of a toll-like receptor complex protein. Nature 457:585–588

    Article  CAS  PubMed  Google Scholar 

  • Uehara A, Fujimoto Y, Fukase K, Takada H (2007) Various human epithelial cells express functional toll-like receptors, NOD1 and NOD2 to produce anti-microbial peptides, but not proinflammatory cytokines. Mol Immunol 44:3100–3111

    Article  CAS  PubMed  Google Scholar 

  • Ungaro R, Fukata M, Hsu D, Hernandez Y, Breglio K, Chen A, Xu R, Sotolongo J, Espana C, Zaias J, Elson G, Mayer L, Kosco-Vilbois M, Abreu MT (2009) A novel toll-like receptor 4 antagonist antibody ameliorates inflammation but impairs mucosal healing in murine colitis. Am J Physiol Gastrointest Liver Physiol 296:G1167–G1179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Van Der Fits L, Mourits S, Voerman JS, Kant M, Boon L, Laman JD, Cornelissen F, Mus AM, Florencia E, Prens EP, Lubberts E (2009) Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol 182:5836–5845

    Article  PubMed  CAS  Google Scholar 

  • Vijay-Kumar M, Wu H, Aitken J, Kolachala VL, Neish AS, Sitaraman SV, Gewirtz AT (2007) Activation of toll-like receptor 3 protects against DSS-induced acute colitis. Inflamm Bowel Dis 13:856–864

    Article  PubMed  Google Scholar 

  • Wakashin H, Hirose K, Maezawa Y, Kagami S, Suto A, Watanabe N, Saito Y, Hatano M, Tokuhisa T, Iwakura Y, Puccetti P, Iwamoto I, Nakajima H (2008) IL-23 and Th17 cells enhance Th2-cell-mediated eosinophilic airway inflammation in mice. Am J Respir Crit Care Med 178:1023–1032

    Article  CAS  PubMed  Google Scholar 

  • Wald D, Qin J, Zhao Z, Qian Y, Naramura M, Tian L, Towne J, Sims JE, Stark GR, Li X (2003) SIGIRR, a negative regulator of toll-like receptor-interleukin 1 receptor signaling. Nat Immunol 4:920–927

    Article  CAS  PubMed  Google Scholar 

  • Walter S, Letiembre M, Liu Y, Heine H, Penke B, Hao W, Bode B, Manietta N, Walter J, Schulz-Schuffer W, Fassbender K (2007) Role of the toll-like receptor 4 in neuroinflammation in Alzheimer’s disease. Cell Physiol Biochem 20:947–956

    Article  CAS  PubMed  Google Scholar 

  • Walter A, Schafer M, Cecconi V, Matter C, Urosevic-Maiwald M, Belloni B, Schonewolf N, Dummer R, Bloch W, Werner S, Beer HD, Knuth A, Van Den Broek M (2013) Aldara activates TLR7-independent immune defence. Nat Commun 4:1560

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Tang Y, Teng L, Wu Y, Zhao X, Pei G (2006) Association of beta-arrestin and TRAF6 negatively regulates toll-like receptor-interleukin 1 receptor signaling. Nat Immunol 7:139–147

    Article  CAS  PubMed  Google Scholar 

  • Watanabe T, Kitani A, Murray PJ, Strober W (2004) NOD2 is a negative regulator of toll-like receptor 2-mediated T helper type 1 responses. Nat Immunol 5:800–808

    Article  CAS  PubMed  Google Scholar 

  • Wu HJ, Sawaya H, Binstadt B, Brickelmaier M, Blasius A, Gorelik L, Mahmood U, Weissleder R, Carulli J, Benoist C, Mathis D (2007) Inflammatory arthritis can be reined in by CpG-induced DC-NK cell cross talk. J Exp Med 204:1911–1922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xavier RJ, Podolsky DK (2007) Unravelling the pathogenesis of inflammatory bowel disease. Nature 448:427–434

    Article  CAS  PubMed  Google Scholar 

  • Xiong Y, Song C, Snyder GA, Sundberg EJ, Medvedev AE (2012) R753Q polymorphism inhibits toll-like receptor (TLR) 2 tyrosine phosphorylation, dimerization with TLR6, and recruitment of myeloid differentiation primary response protein 88. J Biol Chem 287:38327–38337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yamada M, Ichikawa T, Ii M, Sunamoto M, Itoh K, Tamura N, Kitazaki T (2005) Discovery of novel and potent small-molecule inhibitors of NO and cytokine production as antisepsis agents: synthesis and biological activity of alkyl 6-(N-substituted sulfamoyl)cyclohex-1-ene-1-carboxylate. J Med Chem 48:7457–7467

    Article  CAS  PubMed  Google Scholar 

  • Yarilina A, Dicarlo E, Ivashkiv LB (2007) Suppression of the effector phase of inflammatory arthritis by double-stranded RNA is mediated by type I IFNs. J Immunol 178:2204–2211

    Article  CAS  PubMed  Google Scholar 

  • Yesudhas D, Gosu V, Anwar MA, Choi S (2014) Multiple roles of toll-like receptor 4 in colorectal cancer. Front Immunol 5:334

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yoon SI, Kurnasov O, Natarajan V, Hong M, Gudkov AV, Osterman AL, Wilson IA (2012) Structural basis of TLR5-flagellin recognition and signaling. Science 335:859–864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu Y, Hayward GS (2010) The ubiquitin E3 ligase RAUL negatively regulates type I interferon through ubiquitination of the transcription factors IRF7 and IRF3. Immunity 33:863–877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu N, Zhang S, Zuo F, Kang K, Guan M, Xiang L (2009) Cultured human melanocytes express functional toll-like receptors 2–4, 7 and 9. J Dermatol Sci 56:113–120

    Article  CAS  PubMed  Google Scholar 

  • Zarember KA, Godowski PJ (2002) Tissue expression of human toll-like receptors and differential regulation of toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol 168:554–561

    Article  CAS  PubMed  Google Scholar 

  • Zuo L, Lucas K, Fortuna CA, Chuang CC, Best TM (2015) Molecular regulation of toll-like receptors in asthma and COPD. Front Physiol 6:312

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by the Mid-Career Researcher Program through the National Research Foundation of Korea, funded by the Ministry of Education, Science, and Technology (NRF-2015R1A2A2A09001059), and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (HI14C1992). This work was also partially supported by a grant from the Priority Research Centers Program (NRF 2012-0006687).

Author information

Authors and Affiliations

  1. Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea

    Asma Achek, Dhanusha Yesudhas & Sangdun Choi

Authors
  1. Asma Achek
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dhanusha Yesudhas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sangdun Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sangdun Choi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest with the contents of this article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Achek, A., Yesudhas, D. & Choi, S. Toll-like receptors: promising therapeutic targets for inflammatory diseases. Arch. Pharm. Res. 39, 1032–1049 (2016). https://doi.org/10.1007/s12272-016-0806-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-016-0806-9

Keywords

Search

Navigation