Toll-like receptors activation, signaling, and targeting: an overview

Ahmad R, Al-Mass A, Atizado V, Al-Hubail A, Al-Ghimlas F, Bennakhi A, Dermime S, Behbehani K (2012) Elevated expression of the toll like receptors 2 and 4 in obese individuals: its significance for obesity-induced inflammation. J Inflamm 9:48

Ahmed S, Moawad M, Elhefny R, Abdullatif M (2016) Is toll like receptor 4 a common pathway hypothesis for development of lung cancer and idiopathic pulmonary fibrosis? Egypt J Chest Dis Tuberc 65(1):289–294

Akira S, Takeda K (2004) Toll-like receptor signaling. Nat Rev Immunol 4:499–511. https://doi.org/10.1038/nri1391

Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801

Allam HA, Abd EL-Salam M, Mohammad A, Aboulkhair AG (2015) Clinical value of Toll like receptor 4 and CD14 in children with acute lower respiratory tract infection. Int Biol Biomed J Summer 1(3):90–97

Anderson KV, Bokla L, Nusslein-Volhard C (1985) Establishment of dorsal ventral polarity in the Drosophila embryo: the induction of polarity by the Toll gene product. Cell 42:791–798

Arslan F, Houtgraaf JH, Keogh B, Kazemi K, de Jong R (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. https://doi.org/10.1161/CIRCINTERVENTIONS.111.967596

Ayres JS, Schneider DS (2012) Tolerance of infections. Annu Rev Immunol 30:271–294

Babazada H, Yamashita F, Hashida M (2014a) Suppression of experimental arthritis with self-assembling glycol-split heparin nanoparticles via inhibition of TLR4-NF-kappaB signaling. J Control Release 194:295–300. https://doi.org/10.1016/j.jconrel.2014.09.015

Babazada H, Yamashita F, Yanamoto S, Hashida M (2014b) Self-assembling lipid modified glycol-split heparin nanoparticles suppress lipopolysaccharide-induced inflammation through TLR4-NF-kappaB signaling. J Control Release 194:332–340. https://doi.org/10.1016/j.jconrel.2014.09.011

Barochia A, Solomon S, Cui X, Natanson C, Eichacker PQ (2011) Eritoran tetrasodium (E5564) treatment for sepsis: review of preclinical and clinical studies. Drug Metab Toxicol 7:479–494. https://doi.org/10.1517/17425255.2011.558190

Barrat FJ, Meeker T, Gregorio J, Chan JH, Uematsu S, Akira S (2005) Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J Exp Med 202:1131–1139. https://doi.org/10.1084/jem.20050914

Bartel DP (2012) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233. https://doi.org/10.1016/j.cell.2009.01.002

Bassuny YMN. Study of single nucleotide polymorphisms in TLR4 and NOD2 in Egyptian patients with colorectal cancer. MD. Cairo: Cairo University; faculty of pharmacy. Available from: http://erepository.cu.edu.eg/index.php/ cutheses/article/view/7601. 2017.

Bernard NJ, O'Neill LA (2013) Mal, more than a bridge to MyD88. IUBMB Life 65:777–786

Blanco E, Shen H, Ferrari M (2015) Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat Biotechnol 33:941–951. https://doi.org/10.1038/nbt.3330

Blasius AL, Beutler B (2010) Intracellular toll-like receptors. Immunity 32(3):305–315. https://doi.org/10.1016/j.immuni.2010.03.012

Boone DL, Turer EE, Lee EG, Ahmad RC, Wheeler MT, Tsui C (2014) The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol 5:1052–1060

Borges MC, Castro LA, Fonseca BA (2013) Chloroquine use improves dengue-related symptoms. Mem Inst Oswaldo Cruz. 108:596–599. https://doi.org/10.1590/S0074-02762013000500010

Bresnahan KA, Tanumihardjo SA (2014) Undernutrition, the acute phase response to infection, and its effects on micronutrient status indicators. Adv Nutr 5(6):702–711 https://doi.org/10.3945/an.114.006361

Brikos C, O’Neill LAJ. Signaling of Toll-like receptors and innate immunity 22-41. Handbook of Experimental Pharmacology, Volume 183 Stefan Bauer Gunther Hartmann (eds). 2008.

Brint EK, Xu D, Liu H, Dunne A, McKenzie AN, O'Neill LA (2004) ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance. Nat Immunol 5:373–379

Bryant CE, Symmons M, Gay NJ (2015) Toll-like receptor signaling through macromolecular protein complexes. Mol Immunol 63:162–165

Burns K, Janssens S, Vercammen E, Tschopp J (2003) Inhibition of interleukin 1 receptor/Toll-like receptor signaling through the alternatively spliced, short form of MyD88 is due to its failure to recruit IRAK-4. J Exp Med 197:263–268

Cavalcante P, Barzago C, Baggi F, Antozzi C, Maggi L, Mantegazza R, Bernasconi P (2018) Toll-like receptors 7 and 9 in myasthenia gravis thymus: amplifiers of autoimmunity? Ann N Y Acad Sci 1413(1):11–24. https://doi.org/10.1111/nyas.13534

Cole JE, Georgiou E, Monaco C (2010) The expression and functions of toll-like receptors in atherosclerosis. Mediators Inflamm 393946

Couillault C, Pujol N, Reboul J, Sabatier L, Guichou JF, Kohara Y, Ewbank JJ (2004) TLR-independent control of innate immunity in Caenorhabditis elegans by the TIR domain adaptor protein TIR-1, an ortholog of human SARM. Nature Immunol 5:488–494

Cui G, Ye X, Zuo T, Zhao H, Zhao Q, Chen W (2013) Chloroquine pretreatment inhibits toll-like receptor 3 signaling after stroke. Neurosci Lett 548:101–104. https://doi.org/10.1016/j.neulet.2013.02.072

Cusson-Hermance N, Khurana S, Lee TH, Fitzgerald KA, Kelliher MA (2005) RIP1 mediates the TRIF-dependent Toll-like receptor 3- and 4-induced NF-κB activation but does not contribute to interferon regulatory factor 3 activation. J Biol Chem 280:36560–36566

Dagvadorj J, Shimada K, Chen S, Jones HD, Tumurkhuu G, Zhang W (2015) Lipopolysaccharide induces alveolar macrophage necrosis via CD14 and the P2X7 receptor leading to interleukin-1α release. Immunity 42:640–653. https://doi.org/10.1016/j.immuni.2015.03.007

Daubeuf B, Mathison J, Spiller S, Hugues S, Herren S, Ferlin W (2007) TLR4/MD-2 monoclonal antibody therapy affords protection in experimental models of septic shock. J Immunol 179:6107–6114. https://doi.org/10.4049/jimmunol.179.9.6107

Delneste Y, Beauvillain C, Jeannin P (2007) Innate immunity: structure and function of TLRs. Med Sci (Paris) 23(1):67–73. https://doi.org/10.1051/medsci/200723167

Devaraj S, Yun JM, Duncan Staley CR, Jialal I (2011) Low vitamin D levels correlate with the proinflammatory state in type 1 diabetic subjects with and without microvascular complications. Am J Clin Pathol 135:429–433

Do JE, Kwon SY, Park S, Lee ES (2008) Effects of vitamin D on expression of toll-like receptors of monocytes from patients with Behcet’s disease. Rheumatol Oxf Engl 47:840–848

Dolasia K, Bisht MK, Pradhan G, Udgata A, Mukhopadhyay S. TLRs/NLRs: shaping the landscape of host immunity. Int Rev Immunol. 2018. 37(1): 3-19. doi.org/https://doi.org/10.1080/08830185.2017.1397656.

Donath MY, Shoelson SE, Kim JJ (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11:98–107

Fang D, Yang S, Quan W, Jia H, Quan Z, Qu Z (2014) Atorvastatin suppresses toll-like receptor 4 expression and NF-κB activation in rabbit atherosclerotic plaques. Eur Rev Med Pharmacol Sci 18:242–246

Fathy WM, Soliman MA, Ragheb A, Al-Ashram GH. Study of toll-like receptor 4 in type 2 diabetic patients with or without nephropathy. Menoufia Medical Journal J. 2016. 29 (1): 167-173.

Foit L, Thaxton CS (2016) Synthetic high-density lipoprotein-like nanoparticles potently inhibit cell signaling and production of inflammatory mediators induced by lipopolysaccharide binding Toll-like receptor 4. Biomaterials 100:67–75. https://doi.org/10.1016/j.biomaterials.2016.05.021

Gao W, Xiong Y, Li Q, Yang H (2017) Inhibition of Toll-like receptor signaling as a promising therapy for inflammatory diseases: a journey from molecular to nano therapeutics. Front Physiol 8:508–517. https://doi.org/10.3389/fphys.2017.00508

Gauthier MEA, Du Pasquier L, Degnan BM (2010) The genome of the sponge Amphimedon queenslandica provides new perspective into the origin of Toll-like and interleukin 1 pathways. Evol Dev 12:519–533

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

Golshiri-Isfahani A, Amizadeh M, Arababadi MK (2018) The roles of toll like receptor 3, 7 and 8 in allergic rhinitis pathogenesis. Allergol Immunopathol S0301-0546(17):30186–30186. https://doi.org/10.1016/j.aller.2017.09.026

Gomez-Guzman M, Jimenez R, Romero M, Sanchez M, Zarzuelo MJ, Gomez-Morales M (2014) Chronic hydroxychloroquine improves endothelial dysfunction and protects kidney in a mouse model of systemic lupus erythematosus. Hypertension 64:330–337. https://doi.org/10.1161/114.03587

Goulopoulou S, McCarthy CG, Webb RC (2016) Toll-like receptors in the vascular system: sensing the dangers within. Pharmacol Rev 68(1):142–167. https://doi.org/10.1124/pr.114.010090

Guiducci C, Gong M, Xu Z, Gill M, Chaussabel D, Meeker T (2010) TLR recognition of self-nucleic acids hampers glucocorticoid activity in lupus. Nature 465:937–941. https://doi.org/10.1038/nature09102

Guo L, Ai J, Zheng Z, Howatt DA, Daugherty A, Huang B (2013) High density lipoprotein protects against polymicrobe-induced sepsis in mice. J Biol Chem 288:17947–17953. https://doi.org/10.1074/jbc.M112.442699

Hatterer E, Shang L, Simonet P, Herren S, Daubeuf B, Teixeira S (2016) A specific anti-citrullinated protein antibody profile identifies a group of rheumatoid arthritis patients with a toll-like receptor 4-mediated disease. Arthritis Res Ther 18:224. https://doi.org/10.1186/s13075-016-1128-5

He X, Jing Z, Cheng G (2014) MicroRNAs: new regulators of Toll-like receptor signalling pathways. Biomed Res Int 945169. https://doi.org/10.1155/2014/945169

Heijden IM, Wilbrink B, Tchetverikov I (1998) Presence of bacterial DNA and bacterial peptidoglycans in the joints of patients with rheumatoid arthritis and other arthritis’s. Arthritis Rheum 41(9):S162

Hemmi H, Takeuchi O, Kawai T (2000) A Toll-like receptor recognizes bacterial DNA. Nature 408(6813):740–745. https://doi.org/10.1038/35047123

Hoebe K, Du X, Georgel P (2003) Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424(6950):743–748

Huang QQ, Pope RM (2009) Role of Toll like receptors in rheumatoid arthritis. Curr Rheumatol Rep. 11(5):357–364

Hussein YM, Awad HA, Shalaby SM, Ali AA, Alzahrani SS (2012) Toll-like receptor 2 and Toll-like receptor 4 polymorphisms and susceptibility to asthma and allergic rhinitis: a case–control analysis. Cellular Immunol 274(1–2):34–38

Isaza-Correa JM, Zheng Liang Z, van den Berg A, Arjan Diepstra A, Lydia VL (2014) Toll-like receptors in the pathogenesis of human B cell malignancies. J Hematol Oncol 7:57. https://doi.org/10.1186/s13045-014-0057-5

Ishibashi M, Sayers S, D'Armiento JM, Tall AR, Welch CL (2013) TLR3 deficiency protects against collagen degradation and medial destruction in murine atherosclerotic plaques. Atherosclerosis 229:52–61

Iwami KI, Matsuguchi T, Masuda A, Kikuchi T, Musikacharoen T, Yoshikai Y (2000) Cutting edge: naturally occurring soluble form of mouse Toll-like receptor 4 inhibits lipopolysaccharide signaling. J Immunol 165:6682–6686

Jaffer U, Wade RG, Gourlay T (2010) Cytokines in the systemic inflammatory response syndrome: a review. HSR Proc Intensive Care Cardiovasc Anesth 2(3):161–175

Jialal I, Kaur H, Devaraj S (2015) Toll-like receptor status in obesity and metabolic syndrome: a translational perspective. J Clin Endocrinol Metab 99(1):39–48. https://doi.org/10.1210/jc.2013-3092

Kagan J. Signaling organelles of the innate immune system. Cell. 2012. 7; 151(6): 1168–1178. doi: https://doi.org/10.1016/j.cell.2012.11.011.

Kaiser WJ, Offermann MK (2005) Apoptosis induced by the toll-like receptor adaptor TRIF is dependent on its receptor interacting protein homotypic interaction motif. J Immunol 174(8):4942–4952

Karaali ZE, Candan G, Aktuğlu MB, Velet M, Ergen A (2019) Toll-like receptor 2 (TLR-2) gene polymorphisms in type 2 diabetes mellitus. Cell J 20(4):559–563. https://doi.org/10.22074/cellj.2019.5540

Kawai T, Akira S (2010) Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Nat Immunol 11(5):373–384. https://doi.org/10.1038/ni.1863

Kawai T, Akira S. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 2011. 34(5): 637-650. doi.org/https://doi.org/10.1016/j.immuni.2011.05.006.

Kesar V, Odin JA (2014) Toll-like receptors and liver disease. Liver Int 34(2):184–196. https://doi.org/10.1111/liv.12315

Kobayashi K, Hernandez LD, Galán JE, Janeway CA Jr, Medzhitov R, Flavell RA (2012) IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 110:191–202

Komurcu HF, Kilic N, Demirbilek ME, Akin KO (2016) Plasma levels of vitamin B12, epidermal growth factor and tumor necrosis factor alpha in patients with Alzheimer dementia. Int J Res Med Sci 4(3):734–738

Kono DH, Haraldsson MK, Lawson BR, Pollard KM, Koh YT, Du X (2009) Endosomal TLR signaling is required for anti-nucleic acid and rheumatoid factor autoantibodies in lupus. Proc Natl Acad Sci 106:12061–12066. https://doi.org/10.1073/pnas.0905441106

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

Kuznik A, Bencina M, Svajger U, Jeras M, Rozman B, Jerala R (2011) Mechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines. J Immunol 186:4794–4804. https://doi.org/10.4049/jimmunol.1000702

Lancaster GI, Khan Q, Drysdale P, Wallace W, Jeukendrup AE, Drayson MT, Gleeson M (2005) The physiological regulation of toll-like receptor expression and function in humans. J Physiol 563(3):945–955. https://doi.org/10.1113/jphysiol.2004.081224

Leavy O (2011) Innate immunity: SHP regulates TLR signalling. Nat Rev Immunol 11:502

LeBouder E, Rey-Nores JE, Rushmere NK, Grigorov M, Lawn SD, Affolter M (2003) Soluble forms of Toll-like receptor (TLR)2 capable of modulating TLR2 signaling are present in human plasma and breast milk. J Immunol 171:6680–6689

Lee YH, Choi SJ, Ji JD, Song GG (2016) Association between toll-like receptor polymorphisms and systemic lupus erythematous: a meta-analysis update. Lupus 25:593–601. https://doi.org/10.1177/0961203315622823

Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann LA (1996) The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973–983

Li X, Jiang S, Tapping RI (2010) Toll-like receptor signaling in cell proliferation and survival. Cytokine 49:1–9. https://doi.org/10.1016/j.cyto.2009.08.010

Lima CX, Souza DG, Amaral FA, Fagundes CT, Rodrigues IP, Alves-Filho JC (2015) Therapeutic effects of treatment with anti-TLR2 and anti-TLR4 monoclonal antibodies in polymicrobial sepsis. PLoS ONE 10:e0132336. https://doi.org/10.1371/journal.pone.0132336

Lipford G, Forsbach A, Zepp C, Nguyen T, Weeratna R, McCluskie M. “Selective toll-like receptor 7/8/9 antagonists for the oral treatment of autoimmune diseases,” in American College of Rheumatology 2007 Annual Scientific Meeting (Boston, MA). 2017.

Lu X, Xu Q, Bu X, Ma X, Zhang F, Deng Q, Zhang Y, Ding J (2014) Relationship between expression of toll-like receptors 2/4 in dendritic cells and chronic hepatitis B virus infection. Int J Clin Exper Pathol 7(9):6048–6055

Lyn-Cook BD, Xie C, Oates J, Treadwell E, Word B, Hammons G (2014) Increased expression of Toll-like receptors (TLRs) 7 and 9 and other cytokines in systemic lupus erythematous (SLE) patients: ethnic differences and potential new targets for therapeutic drugs. Mol Immunol 61:38–43. https://doi.org/10.1016/j.molimm.2014.05.001

Mahla RS (2013) Sweeten PAMPs: role of sugar complexed PAMPs in innate immunity and vaccine biology. Front Immunol 4:248. https://doi.org/10.3389/fimmu.2013.00248

Mansell A, Brint E, Gould JA, O'Neill LA, Hertzog PJ (2004) Mal interacts with tumor necrosis factor receptor-associated factor (TRAF)-6 to mediate NF-κB activation by Toll-like receptor (TLR)-2 and TLR4. J Biol Chem 279:37227–37230

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. https://doi.org/10.1124/mol.110.068064

McCarthy CG, Wenceslau CF, Goulopoulou S, Ogbi S, Baban B, Sullivan JC (2015) Circulating mitochondrial DNA and Toll-like receptor 9 are associated with vascular dysfunction in spontaneously hypertensive rats. Cardiovasc Res 107:119–130. https://doi.org/10.1093/cvr/cvv137

McGettrick AF, Brint EK, Palsson-McDermott EM, Rowe DC, Golenbock DT, Gay NJ, Fitzgerald KA, O’Neill LAJ (2006) TRIF-related adapter molecule is phosphorylated by PKCε during Toll-like receptor 4 signaling. Proc Natl Acad Sci 103:9196–9201

Medzhitov R, Preston-Hurlburt P, Janeway CA (1997) A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388:394–397

Meng G, Rutz M, Schiemann M, Metzger J, Grabiec A, Schwandner R (2004) Antagonistic antibody prevents toll-like receptor 2-driven lethal shock-like syndromes. J Clin Invest. 113:1473–1481. https://doi.org/10.1172/JCI20762

Mohamed ZAZ, Abd-Elraheem SE, El-Nahrery EMA, Sabry S, Mohamed MSE (2016) TLR2 and IL 18 in obese diabetic patienT. J Diabetes Metab 7:5. https://doi.org/10.4172/2155-6156.1000672

Monnet E, Lapeyre G, Poelgeest EV, Jacqmin P, Graaf K, Reijers J (2017) NI-0101, a monoclonal antibody targeting toll like receptor 4 (TLR4) being developed for rheumatoid arthritis (RA) treatment with a potential for personalized medicine. Clin Pharmacol Ther 101:200–208. https://doi.org/10.1002/cpt.522

Monnet E, Shang L, Lapeyre G, de Graaf K, Hatterer E, Buatois V (2015) Evidence of NI-0101 pharmacological activity, an anti-TLR4 antibody, in a randomized phase I dose escalation study in healthy volunteers receiving LPS. Ann Rheum Dis 74:1. https://doi.org/10.1136/annrheumdis-2015-eular.3801

Moresco EM, LaVine D, Beutler B (2011) Toll-like receptors. Curr Biol 21(13):R488–R493

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

Nadeem A, Ahmad SF, Bakheet SA, Al-Harbi NO, Al-Ayadhi LY, Attia SM, Zoheir KMA (2017) Toll-like receptor 4 signaling is associated with upregulated NADPH oxidase expression in peripheral T cells of children with autism. Brain Behav Immun 61:146–154. https://doi.org/10.1016/j.bbi.2016.12.024

Opal SM, Laterre PF, Francois B, LaRosa SP, Angus DC, Mira JP (2013) Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. JAMA 309:1154–1162. https://doi.org/10.1001/jama.2013.2194

Pedrosa P, Vinhas R, Fernandes A, Baptista PV (2015) Gold nanotheranostics: proof-of-concept or clinical tool? Nanomaterials 5:1853–1879. https://doi.org/10.3390/nano5041853

Pereira DV, Petronilho F, Pereira HR, Vuolo F, Mina F, Possato JC (2012) Effects of gold nanoparticles on endotoxin-induced uveitis in rats. Invest Ophthalmol Vis Sci 53:8036–8041. https://doi.org/10.1167/iovs.12-10743

Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X (1998) Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in TLR4 gene. Science 282:2085–2088

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

Re F, Strominger JL (2011) Toll-like receptor 2 (TLR2) and TLR4 differentially activate human dendritic cells. J Biol Chem 276:37692–37699. https://doi.org/10.1074/jbc.M105927200

Rodriguez Lavado J, Sestito SE, Cighetti R, Aguilar Moncayo EM, Oblak A, Lainscek D (2014) Trehalose- and glucose-derived glycoamphiphiles: small-molecule and nanoparticle Toll-like receptor 4 (TLR4) modulators. J Med Chem 57:9105–9123. https://doi.org/10.1021/jm501182w

Roelofst MF, Joosten LA, Abdollahi-Roodsaz S, van Lieshout AW, Sprong T, van den Hoogen FH (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(8):2313–2322

Rommler F, Hammel M, Waldhuber A, Muller T, Jurk M, Uhlmann E (2015) Guanine-modified inhibitory oligonucleotides efficiently impair TLR7- and TLR9-mediated immune responses of human immune cells. PLoS ONE 10:e0116703. https://doi.org/10.1371/journal.pone.0116703

Sadik NA, Shaker OG, Ghanem HZ, Hassan HA, Abdel-Hamid AH (2015) Single-nucleotide polymorphism of Toll-like receptor 4 and interleukin-10 in response to interferon-based therapy in Egyptian chronic hepatitis C patients. Arch Virol. 160(9):2181–2195. https://doi.org/10.1007/s00705-015-2493-0

Schneider DS, Hudson KL, Lin TY, Anderson KV (1991) Dominant and recessive mutations define functional domains of Toll, a Trans membrane protein required for dorsal-ventral polarity in the Drosophila embryo. Genes Dev 5:797–807

Sellge G, Kufer TA (2015) PRR-signaling pathways: learning from microbial tactics. Semin Immunol 27:75–84

Sepehri Z,Kiani Z,Nasiri AA, andKohan F. Toll-like receptor 2 and type 2 diabetes. Cell Mol Biol Lett 2016; 21: 2. doi: https://doi.org/10.1186/s11658-016-0002-4

Sharma N, Akhade AS, Qadri A (2013) Sphingosine-1-phosphate suppresses TLR-induced CXCL8 secretion from human T cells. J Leukoc Biol 93(4):521–528. https://doi.org/10.1189/jlb.0712328

Shen N, Liang D, Tang Y, de Vries N, Tak PP (2016) MicroRNAs–novel regulators of systemic lupus erythematosus pathogenesis. Nat Rev Rheumatol 8:701–709. https://doi.org/10.1038/nrrheum.2012.142

Sindhu S, Akhter N, Kochumon S, Thomas R, Wilson A, Shenouda S, Tuomilehto J (2018) Increased expression of the innate immune receptor TLR10 in obesity and type-2 diabetes: association with ROS-mediated oxidative stress. Cell Physiol Biochem 45:572–590 https://doi.org/10.1159/000487034

Singh K, Kant S, Gupta SK, Singh VK (2014) Toll-like receptor 4 polymorphisms and their haplotypes modulate the risk of developing diabetic retinopathy in type 2 diabetes patients. Mol Vision 20:704–713

So EY, Ouchi T (2010) The application of toll like receptors for cancer therapy. Int J Biol Sci 6(7):675–681

Soliman OE, Shaltout AA, Hasaneen BM, Mosaad AE, Mosaad YM (2014) Toll-like receptors genotype polymorphism in Egyptian children with chronic viral hepatitis C. Arch Dis Child 99(2):A1–A620 doi.org/10.1136/archdischild-2014-307384.294

Spiller S, Elson G, Ferstl R, Dreher S, Mueller T, Freudenberg M (2008) TLR4-induced IFN-gamma production increases TLR2 sensitivity and drives Gram-negative sepsis in mice. J Exp Med 205:1747–1754. https://doi.org/10.1084/jem.20071990

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. https://doi.org/10.1371/journal.pone.0084634

Subramanian S, Tus K, Li QZ, Wang A, Tian XH, Zhou J (2006) A TLR7 translocation accelerates systemic autoimmunity in murine lupus. Proc Natl Acad Sci USA 103:9970–9975. https://doi.org/10.1073/pnas.0603912103

Takeda K, Akira S. Toll-like receptors. In: Coligan John E, et al., editors. Current protocols in immunology. 2015. 109: 1421–20.

Takeda K, Georgel P, Janssen E (2004) Toll like receptor and their ligands. Proc Natl Acad Sci 101(10):3516–3521. https://doi.org/10.1073/pnas.0400525101

Troutman TD, Hu W, Fulenchek S, Yamazaki T, Kurosaki T, Bazan JF (2012) Role for B-cell adapter for PI3K (BCAP) as a signaling adapter linking Toll-like receptors (TLRs) to serine/threonine kinases PI3K/Akt. Proc Natl Acad Sci 109:273–278

Tsujimoto H, Ono S, Efron PA, Scumpia PO, Moldawer LL, Mochizuki H (2008) Role of Toll-like receptors in the development of sepsis. Shock 29(3):315–321. https://doi.org/10.1097/SHK.0b013e318157ee55

Vidya MK, Kumar VG, Sejian V, Bagath M, Krishnan G, Bhatta R (2017) Toll-like receptors: significance, ligands, signaling pathways, and functions in mammals. Int Rev Immunol 37(3):1–17 doi.org/10.1080/08830185.2017.1380200

Wang Y, Song E, Bai B, Vanhoutte PM. Toll-like receptors mediating vascular malfunction: lessons from receptor subtypes. Pharm & Therap 2015. In press. doi.org/10.1016/j.pharmthera.2015.12.005.

Wang YC, Lin S, Yang QW (2011) Toll-like receptors in cerebral ischemic inflammatory injury. J Neuroinflammation 8:134. https://doi.org/10.1186/1742-2094-8-134

Wong SW, Kwon MJ, Choi AM, Kim HP, Nakahira K, Hwang DH (2009) Fatty acids modulate toll-like receptor 4 activation through regulation of receptor dimerization and recruitment into lipid rafts in a reactive oxygen species-dependent manner. J Biol Chem 284:27384–27392

Wu Y, He S, Bai B, Zhang L, Xue L, Lin Z (2016) Therapeutic effects of the artemisinin analog SM934 on lupus-prone MRL/lpr mice via inhibition of TLR-triggered B-cell activation and plasma cell formation. Cell Mol Immunol 13:379–390. https://doi.org/10.1038/cmi.2015.13

Yamamoto M, Sato S, Hemmi H, Sanjo H, Uematsu S, Kaisho T (2002) Cutting edge: a novel Toll/IL-1 receptor domain-containing adaptor that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. J Immunol 169(12):6668–6672

Yamamoto M, Takeda K (2010) Current views of toll-like receptor signaling pathways. Gastroenterol Res Pract 240365. https://doi.org/10.1155/2010/240365

Yang H, Kozicky L, Saferali A, Fung SY, Afacan N, Cai B (2016) Endosomal pH modulation by peptide-gold nanoparticle hybrids enables potent anti-inflammatory activity in phagocytic immune cells. Biomaterials 111:90–102 doi.org/10.1016/j.biomaterials.2016.09.032

Yasuda H, Leelahavanichkul A, Tsunoda S, Dear JW, Takahashi Y, Ito S (2018) Chloroquine and inhibition of Toll-like receptor 9 protect from sepsis-induced acute kidney injury. Am J Physiol Renal Physiol 294:F1050–F1058. https://doi.org/10.1152/ajprenal.00461.2007

Yin J, Peng Y, Wu J, Wang Y, Yao L (2014) Toll-like receptor 2/4 links to free fatty acid-induced inflammation and beta-cell dysfunction. J Leukoc Biol 95:47–52

Yu L, Feng Z (2018) The role of toll-like receptor signalling in the progression of heart failure. Mediators Inflamm 8:9874109. https://doi.org/10.1155/2018/9874109

Yuk JM, Jo EK (2011) Toll-like receptors and innate immunity. J Bacteriol Virol 41(4):225–235

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(2):554–561

Zhang Y, Liang C (2016) Innate recognition of microbial-derived signals in immunity and inflammation. Sci China Life Sci 59(12):1210–1217. https://doi.org/10.1007/s11427-016-0325-6

Zhang YW, Thompson R, Zhang H, Xu H (2011) APP processing in Alzheimer’s disease. Mol Brain 4:3–11. https://doi.org/10.1186/1756-6606-4-3

Zhao GN, Jiang DS, Li HL. Interferon regulatory factors: at the crossroads of immunity, metabolism, and disease. Biochimica et Biophysica Acta. 2015. 1852(2): 365 378. doi.org/https://doi.org/10.1016/j.bbadis.2014.04.030.

Zhao M, Li CH, Liu YL (2016) Toll-like receptor (TLR)-2/4 expression in retinal ganglion cells in a high-glucose environment and its implications. Genet Mol Res 15(2):23–41

Zhu F, Jiang W, Dong Y, Kandimalla E, La Monica N, Agrawal S (2012) IMO-8400, a novel TLR7, TLR8 and TLR9 antagonist, inhibits disease development in lupus-prone NZBW/F1 mice. J Immunol 188(1):109–112

Ziegler G, Freyer D, Harhausen D, Khojasteh U, Nietfeld W, Trendelenburg G (2011) Blocking TLR2 in vivo protects against accumulation of inflammatory cells and neuronal injury in experimental stroke. J Cereb Blood Flow Metab 31:757–766. https://doi.org/10.1038/jcbfm.2010.161

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