Role Of Toll Like Receptors In Various Diseases

Abstract

Toll like receptors are the innate immune receptors, responsible for the identification of pathogens. Ten different toll like receptors have been described in humans. Toll-like receptors are being activated by both exogenous ligands (bacterial, viral ve fungal pathogens) and endogenous ligands released from damaged cells. The several of studies show that toll like receptors signaling is important in the pathogenesis of disease as cancer, diabetes mellitus, atherosclerosis, renal disease, gastrointestinal disease, lung disease, central nervous system disease, autoimmune disease. The aim of this review is to define the role of toll like receptors in the pathogenesis of various diseases.

Keywords

• TLR, TLR ligands, diseases

Çeşitli Hastalıklarda Toll Benzeri Reseptörlerin Rolü

Abstract

Toll benzeri reseptörler, patojenlerin tanınmasından sorumlu doğal immün reseptörlerdir. İnsanlarda on farklı toll benzeri reseptör tanımlanmıştır. Toll benzeri reseptörler çeşitli hastalıklarda ekzojen ligandlar (bakteriyel, viral ve fungal patojenler) ve hücre hasarı sonucu salınan endojen ligandlar ile aktive olur. Birçok çalışma toll benzeri reseptör sinyalizasyonunun kanser, diyabet, ateroskleroz, böbrek hastalıkları, gastrointestinal hastalıklar, akciğer hastalıkları, santral sinir sistemi hastalıkları, otoimmün hastalıklar gibi hastalıkların patogenezinde önemli olduğunu göstermektedir. Bu derlemenin amacı çeşitli hastalıkların patogenezinde toll benzeri reseptörlerin oynadığı rolü tanımlamaktır.

Keywords

• TLR, TLR ligandları, hastalıklar

References

1. Hashimoto C, Hudson KL, Anderson KV. The Toll gene of Drosophila, required for dorsal-ventral embryonic polarity, appears to encode a transmembrane protein. Cell 1988;52:269–279.
2. Lemaitre B, Nicolas E, Michaut L, Reichhart J-M, Hoffmann JA. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 1996;86:973-983.
3. Taguchi T, Mitcham JL, Dower SK, Sims JE, Testa JR. Chromosomal Localization ofTIL, a Gene Encoding a Protein Related to the Drosophila Transmembrane Receptor Toll, to Human Chromosome 4p14. Genomics. 1996;15;32(3):486-488.
4. Akira S. Toll-like Receptor Signaling. The Journal Of Biological Chemistry 2003;278, 40(3):38105-38108.
5. Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol 2003;21:335–76.
6. Shimizu T, Kida Y, and Kuwano K. Triacylated lipoproteins derived from Mycoplasma pneumoniae activate nuclear factor-κB through Toll-like receptors 1 and 2. Immunology 2007;121(4):473-483.
7. Wyllie DH, Kiss-Toth E, Visintin A, Smith SC, Boussouf S, Segal DM et al. Evidence for an accessory protein function for Toll- like receptor 1 in antibacterial responses. Journal of Immunology 2000;165(12):7125–7132.
8. Takeuchi O, Kaufmann A, Grote K. Cutting edge: preferentially the R-stereoisomer of the mycoplasmal lipopeptide macrophage- activating lipopeptide-2 activates immune cells through a Toll-like receptor 2- and MyD88-dependent signaling pathway. J Immunol 2000;164:554-557.

9. Nijhuis MMO, Pasterkamp G, Sluis NI, De Kleijn DPV, Laman JD, and Ulfman LH. Peptidoglycan increases firm adhesion of monocytes under flow conditions and primes monocyte chemotaxis. Journal of Vascular Research 2007;44(3):214-222.
10. Roeder A, Kirschning CJ, Rupec RA, Schaller M, Weindl G, Korting HC. Toll-like receptors as key mediators in innate antifungal immunity. Med Mycol. 2004 Dec;42(6):485-98.
11. Bieback K, Lien E, Klagge IM, Avota E, Schneider-Schaulies J, Duprex WP et al. Hemagglutinin protein of wild-type measles virus activates Toll-like receptor 2 signaling. Journal of Virology 2002;76(17):8729-8736.
12. Asea A, Rehli M, Kabingu E, Boch JA, Bare O, Auron PE et al. Novel signal transduction pathway utilized by extracellular HSP70. Role of Tolllike receptor (TLR) 2 and TLR4. The Journal of Biological Chemistry 2002;277(17):15028-34.
13. Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, Ishizaka A et al. Involvement of Toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. The Journal of Biological Chemistry 2004;279(9):7370-7.
14. Vabulas RM, Ahmad-Nejad P, da Costa C, Miethke T, Kirschning CJ, Häcker H et al. Endocytosed HSP60s use Toll-like receptor 2 (TLR2) and TLR4 to activate the toll/interleukin-1 receptor signaling pathway in innate immune cells. The Journal of Biological Chemistry 2001;276(33):31332-9.
15. Li M, Carpio DF, Zheng Y, Bruzzo P, Singh V, Ouaaz F et al. An essential role of the NF-κB/Toll-like receptor pathway in induction of inflammatory and tissue-repair gene expression by necrotic cells. Journal of Immunology 2001;166(12):7128-7135.
16. Kawakami A, Osaka M, Aikawa M, Uematsu S, Akira S, Libby P et al. Toll-like receptor 2 mediates apolipoprotein CIII-induced monocyte activation. Circulation Research 2008;103(12):1402- 1409.
17. Holvoet P, Davey PC, De Keyzer D, Doukouré M, Deridder E, Bochaton-Piallat ML et al. Oxidized low-density lipoprotein correlates positively with Toll-like receptor 2 and interferon regulatory factor-1 and inversely with superoxide dismutase-1 expression: studies in hypercholesterolemic swine and THP- 1 cells. Arteriosclerosis, Thrombosis, and Vascular Biology 2006;26(7):1558-1565.
18. Cheng N, He R, Tian J, Ye PP, and Ye RD. Cutting edge: TLR2 is a functional receptor for acute-phase serum amyloid A. Journal of Immunology 2008;181(1):22-26.
19. Jana M, Palencia CA, and Pahan K. Fibrillar amyloid- κ peptides activate microglia via TLR2: implications for Alzheimer’s disease. Journal of Immunology 2008;18(10):7254-7262.
20. Kariko K, Ni H, Capodici J, Lamphier M, and Weissman D. mRNA is an endogenous ligand for Toll-like receptor 3. The Journal of Biological Chemistry 2004;279(13):12542-12550.
21. Alexopoulou L, Holt AC, Medzhitov R, and Flavell RA. Recognition of double-stranded RNA and activation of NF- κB by Toll-like receptor 3. Nature 2001;413(6857):732-738.
22. Smith KD. Toll-like receptors in kidney disease. Curr Opin Nephrol Hypertens. 2009;18(3):189-196.
23. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998;282(5396):2085-2088.
24. Kurt-Jones EA, Popova L, Kwinn L, Haynes LM, Jones LP, Tripp RA et al. Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nature Immunology 2000;1(5):398-401.
25. Okamura Y, Watari M, Jerud ES, Young DW, Ishizaka ST, Rose J et al. The extra domain A of fibronectin activates Toll-like receptor 4. The Journal of Biological Chemistry 2001;276(13):10229- 10233.
26. Taylor KR, Trowbridge JM, Rudisill JA, Termeer CC, Simon JC, and Gallo RL. Hyaluronan fragments stimulate endothelial recognition of injury through TLR4. The Journal of Biological Chemistry 2004;279(17):17079-17084.
27. Kodaira Y, Nair SK, Wrenshall LE, Gilboa E, and Platt JL. Phenotypic and functional maturation of dendritic cells mediated by heparan sulfate. Journal of Immunology 2000;165(3):1599-1604.
28. Hodgkinson CP, Patel K, and Ye S. Functional Toll-like receptor 4 mutations modulate the response to fibrinogen. Thrombosis and Haemostasis 2008;100(2):301-307.
29. Biragyn A, Ruffini PA, Leifer CA, Klyushnenkova E, Shakhov A, Chertov O, et al. Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2. Science 2002;298(5595):1025– 1029.
30. Xu XH, Shah PK, Faure E, Equils O, Thomas L, Fishbein MC et al. Toll-like receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL. Circulation 2001;104(25):3103-3108.
31. Guillot L, Balloy V, McCormack FX, Golenbock DT, Chignard M, and Si-Tahar M. Cutting edge: the immunostimulatory activity of the lung surfactant protein-A involves Tolllike receptor 4. Journal of Immunology 2002;168(12):5989-5992.
32. Midwood K, Sacre S, Piccinini AM, Inglis J, Trebaul A, Chan E et al. Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nature Medicine 2009;15(7):774-780.
33. Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR, et al. The innate immune response to bacterial flagellin is mediated by Tolllike receptor 5. Nature 2001;410(6832):1099-1103.
34. Buwitt-Beckmann U, Heine H, Wiesmüller KH, Jung G, Brock R, Akira S, et al. Toll-like receptor 6-independent signaling by diacylated lipopeptides. European Journal of Immunology 2005;35(1):282-289.
35. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 2004;303(5663):1526–1529.
36. Andreakos E, Foxwell B, and Feldmann M. Is targeting Toll- like receptors and their signaling pathway a useful therapeutic approach Immunological Reviews 2004;202:250-265.
37. cytokine-driven inflammation?
38. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, et al. A Toll-like receptor recognizes bacterial DNA. Nature 2000;408(6813):740-745.
39. Krug A, Luker GD, Barchet W, Leib DA, Akira S, and Colonna M. Herpes simplex virus type 1 activates murine natural interferon-producing cells through Toll-like receptor 9. Blood 2004;103(4):1433-1437.
40. Akira S, Takeda K. Toll-like receptor signalling. Nature reviews 2004; 4: 499-511.
41. O’Neill LAJ. and Bowie A.G. The family of five: TIRdomain- containing adaptors in Toll-like receptor signalling. Nature Reviews Immunology 2007;7(5):353-364.
42. Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 2003;301:640-3.
43. Yamamoto M, Sato S, Hemmi H, Uematsu S, Hoshino K, Kaisho T et al. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat. Immunol. 2003;4:1144-50.
44. Li Q, Withoff S, Verma IM. Inflammation-associated cancer: NF- kappaB is the lynchpin. Trends in immunology 2005;26:318-25.
45. Yoshioka T, Morimoto Y, Iwagaki H, Itoh H, Saito S, Kobayashi N et al. Bacterial lipopolysaccharide induces transforming growth factor beta and hepatocyte growth factor through toll-like receptor 2 in cultured human colon cancer cells. The Journal of international medical research 2001;29:409-20.
46. Chang YJ, Wu MS, Lin JT, Sheu BS, Muta T, Inoue H et al. Induction of cyclooxygenase-2 overexpression in human gastric epithelial cells by Helicobacter pylori involves TLR2/TLR9 and c-Src-dependent nuclear factor-kappaB activation. Molecular pharmacology 2004;66:1465-77.
47. Salaun B, Coste I, Rissoan MC, Lebecque SJ, Renno T. TLR3 can directly trigger apoptosis in human cancer cells. J Immunol 2006;176:4894-901.
48. Furrie E, Macfarlane S, Thomson G, Macfarlane GT. Toll-like receptors-2, -3 and -4 expression patterns on human colon and their regulation by mucosal-associated bacteria. Immunology 2005;115:565-74.
49. Salaun B, Lebecque S, Matikainen S, Rimoldi D, Romero P. Toll-like receptor 3 expressed by melanoma cells as a target for therapy? Clin Cancer Res 2007;13:4565-74.
50. Molteni M, Marabella D, Orlandi C, Rossetti C. Melanoma cell lines are responsive in vitro to lipopolysaccharide and Express TLR-4. Cancer letters 2006;235:75-83.
51. Schmausser B, Andrulis M, Endrich S, Muller-Hermelink HK, Eck M. Toll-like receptors TLR4, TLR5 and TLR9 on gastric carcinoma cells: an implication for interaction with Helicobacter pylori. Int J Med Microbiol 2005;295:179-85.
52. He W, Liu Q, Wang L, Chen W, Li N, Cao X. TLR4 signaling promotes immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance. Mol Immunol 2007;44:2850-9.
53. Seki E, Brenner DA. Toll-like receptors and adaptor molecules in liver disease. Hepatology 2008;48:322-35.
54. Kelly MG, Alvero AB, Chen R, Silasi DA, Abrahams VM, Chan S et al. TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer research 2006;66:3859-68.
55. Kim WY, Lee JW, Choi JJ, Choi CH, Kim TJ, Kim BG et al. Increased expression of Toll-like receptor 5 during progression of cervical neoplasia. Int J Gynecol Cancer 2008;18:300-5.
56. Koski GK, Czerniecki BJ. Combining innate immunity with radiation therapy for cancer treatment. Clin Cancer Res 2005;11:7-11.
57. Merrell MA, Ilvesaro JM, Lehtonen N, Sorsa T, Gehrs B, Rosenthal E et al. Toll-like receptor 9 agonists promote cellular invasion by increasing matrix metalloproteinase activity. Mol Cancer Res 2006;4:437-47.
58. Xu N, Yao HP, Sun Z, Chen Z. Toll-like receptor 7 and 9 expression in peripheral blood mononuclear cells from patients with chronic hepatitis B and related hepatocellular carcinoma. Acta Pharmacol Sin. 2008;29(2):239-44.
59. El Andaloussi A, Sonabend AM, Han Y, Lesniak MS. Stimulation of TLR9 with CpG ODN enhances apoptosis of glioma and prolongs the survival of mice with experimental brain tumors. Glia 2006;54:526-35.
60. Ilvesaro JM, Merrell MA, Swain TM, Davidson J, Zayzafoon M, Harris KW et al. Toll like receptor-9 agonists stimulate prostate cancer invasion in vitro. The Prostate 2007;67:774-81.
61. Fukata M, Chen A, Vamadevan AS, Cohen J, Breglio K, Krishnareddy S et al. Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology. 2007;133(6):1869-81.
62. Pikarsky E, Porat RM, Stein I Abramovitch R, Amit S, Kasem S et al. NF-kappaB functions as a tumour promoter in inflammation- associated cancer. Nature 2004; 431(7007):461-6.
63. Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ et al. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 2004;118:285-96.
64. Taganov KD, Boldin MP, Chang KJ, Baltimore D. NF-kappaB- dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A. 2006;103(33):12481-6.
65. Nakanishi C, Toi M. Nuclear factor-κB inhibitors as sensitizers to anticancer drugs. Nature Reviews Cancer. 2005;5(4):297-309.
66. Kreuz S, Siegmund D, Rumpf JJ, Samel D, Leverkus M, Janssen O et al. NFκB activation by Fas is mediated through FADD, caspase-8, and RIP and is inhibited by FLIP. Journal of Cell Biology. 2004;166(3):369-380.
67. Lien E, Zipris D. The role of Toll-like receptor pathways in the mechanism of type 1 diabetes. Curr Mol Med. 2009;9(1):52-68.
68. Vives-Pi M, Somoza N, Fernández-Alvarez J, Vargas F, Caro P, Alba A et al. Evidence of expression of endotoxin receptors CD14, Toll like receptors TLR4 and TLR2 and associated molecule MD-2 and of sensitivity to endotoxin (LPS) in islet beta cells. Clin. Exp. Immunol. 2003;133:208-218.
69. Dogusan Z, Garcia M, Flamez D, Alexopoulou L, Goldman M, Gysemans C et al. Double-stranded RNA induces pancreatic beta- cell apoptosis by activation of the toll-like receptor 3 and interferon regulatory factor 3 pathways. Diabetes 2008;57:1236–1245.
70. Devaraj S, Jialal I. Increased secretion of IP-10 from monocytes under hyperglycemia in via the TLR2 and TLR4 pathway. Cytokine 2009;47:6-10.
71. Eizirik DL, Colli M, Ortis F. The role of inflammation in insulitis and beta cell loss in type 1 diabetes. Nat Rev Endocrinol 2009;5:219- 226.
72. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 2006;116:3015-25.
73. Tsukumo DM, Carvalho-Filho MA, Carvalheira JB, Prada PO, Hirabara SM, Schenka AA, et al. Loss-offunction mutation in Toll-like receptor 4 prevents dietinduced obesity and insulin resistance. Diabetes 2007;56:1986-98.
74. Frantz S, Ertl G, Bauersachs J. Mechanisms of disease: Toll-like receptors in cardiovascular disease. Nat Clin Pract Cardiovasc Med 2007;4:444-454.
75. Mullick AE, Tobias PS, Curtiss LK: Modulation of atherosclerosis in mice by Toll-like receptor 2. J Clin Invest 2005;115:3149-3156.
76. Michelsen KS, Wong MH, Shah PK, Zhang W, Yano J, Doherty TM et al.. Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc Natl Acad Sci 2004;101:10679- 10684.
77. Geng HL, Lu HQ, Zhang LZ, Zhang H, Zhou L, Wang H et al. Increased expression of Toll like receptor 4 on peripheral-blood mononuclear cells in patients with coronary arteriosclerosis disease. Clinical and Experimental Immunology 2006;143(2):269- 273
78. S. Kuwahata, S. Fujita, K. Orihara, Hamasaki S, Oba R, Hirai H et al. High expression level of Toll-like receptor 2 on monocytes is an important risk factor for arteriosclerotic disease. Atherosclerosis 2010;209(1):248-254.
79. Loppnow H, Werdan K, Buerke M. Vascular cells contribute to atherosclerosis by cytokine and innateimmunity-related inflammatory mechanisms. Innate Immun 2008;14:63-87.
80. Niessner A, Shin MS, Pryshchep O, Goronzy JJ, Chaikof EL, Weyand CM. Synergistic proinflammatory effects of the antiviral cytokine interferon-alpha and toll-like receptor 4 ligands in the atherosclerotic plaque. Circulation 2007;116:2043-2052.
81. Blair PS, Rex S, Vitseva O, Beaulieu L, Tanriverdi K, Chakrabarti S. Stimulation of toll-like receptor 2 in human platelets induces a thrombo-inflammatory response through activation of phosphoinositide 3-kinase. Circ Res 2009;104:346–354.
82. Jayachandran M, Brunn GJ, Karnicki K, Miller RS, Owen WG, Miller VM. In vivo effects of lipopolysaccharide and TLR4 on platelet production and activity: Implications for thrombotic risk. J Appl Physiol 2007;102:429-433.
83. Boyd JH, Mathur S, Wang Y, Bateman RM, Walley KR. Toll-like receptor stimulation in cardiomyocytes decreases contractility and initiates an NF-κB dependent inflammatory response. Cardiovasc Res 2006;72:384-393.
84. Gluba A, Banach M, Hannam S, Mikhailidis DP, Sakowicz A, Rysz J. The role of Toll-like receptors in renal diseases. Nature Reviews Nephrology 2010;6:224-235.
85. Song J, Abraham SN. TLR-mediated immune responses in the urinary tract. Curr Opin Microbiol 2008;11:66-73.
86. Leemans JC, Stokman G, Claessen N. Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney. J Clin Invest 2005;115:2894-2903.
87. Wu H, Chen G, Wyburn KR. TLR4 activation mediates kidney ischemia/reperfusion injury. J Clin Invest 2007;117:2847–2859.
88. Christensen SR, Shupe J, Nickerson K. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity 2006;25:417-428.
89. Testro AG, Visvanathan K. Toll-like receptors and their role in gastrointestinal disease. Journal of Gastroenterology and Hepatology 2009;24:943-954.
90. Cario E, Podolsky DK. Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect. Immun. 2000;68:7010-17.
91. Otte JM, Cario E, Podolsky DK. Mechanisms of cross hyporesponsiveness to Toll-like receptor bacterial ligands in intestinal epithelial cells. Gastroenterology 2004;126:1054-70.
92. Hausmann M, Kiessling S, Mestermann S, G. Webb, T. Spottl, T. Andus et al. Toll-like receptors 2 and 4 are up-regulated during 10 intestinal inflammation.Gastroenterology 2002;122:1987-2000.
93. Szebeni B, Veres G, Dezsofi A, Rusai K, Vannay Á, Mraz M et al. Increased expression of Toll-like receptor (TLR) 2 and TLR4 in the colonic mucosa of children with inflammatory bowel disease. Clin. Exp. Immunol 2008;151:34-41
94. Wills-Karp M, Chiaramonte M. Interleukin-13 in asthma. Curr Opin Pulm Med 2003;9:21-7.
95. Redecke V, Hacker H, Datta SK, Fermin A, Pitha PM, Broide DH, et al. Cutting edge: activation of Toll-like receptor 2 induces a Th2 immune response and promotes experimental asthma. J Immunol 2004;172:2739-43.
96. Van Rijt LS, van Kessel CH, Boogaard I, Lambrecht BN. Respiratory viral infections and asthma pathogenesis: a critical role for dendritic cells? J Clin Virol 2005;34:161-169.
97. Santeliz JV, Van Nest G, Traquina P, Larsen E, Wills-Karp M. Amb a 1-linked CpG oligodeoxynucleotides reverse established airway hyperreponsiveness in a murine model of asthma. J. Allergy Clin. Immunol 2002;109:455–62.
98. Du Q, Zhou LF, Chen Z, Gu XY, Huang M, Yin KS. Imiquimod, a toll like receptor 7 ligand, inhibits airway remodeling in a murine model of chronic asthma. Clin Exp Pharmacol Physiol. 2009;36:43-8.
99. Droemann D, Goldmann T, Tiedje T, Zabel P, Dalhoff K, Schaaf B. Toll-like receptor 2 expression is decreased on alveolar macrophages in cigarette smokers and COPD patients. Respir Res. 2005;6:68.
100. Blohmake CJ, Victor RE, Hirschfeld AF, Elias IM, Hancock DG, Lane CR et al. Innate immunity mediated by TLR5 as a novel antiinflamatory target for cystic fibrosis lung disease. J Immunol. 2008;180:7764-73.
101. Babcock AA, Wirenfeldt M, Holm T, Nielsen HH, Dissing-Olesen L, Toft-Hansen H et al. Toll-like receptor 2 signaling in response to brain injury: An innate bridge to neuroinflammation. J Neurosci 2006;26:12826-12837.
102. Caso JR, Pradillo JM, Hurtado O, Leza JC, Moro MA, Lizasoain I. Toll-like receptor 4 is involved in subacute stress-induced neuroinflammation and in the worsening of experimental stroke. Stroke 2008;39:1314-1320.
103. Zhao W, Beers DR, Henkel JS, Zhang W, Urushitani M, Julien JP, et al. Extracellular mutant SOD1 induces microglial-mediated motoneuron injury. Glia. 2010;15;58(2):231-43.
104. Frank, E. Copanaki, G.J. Burbach, U.C. Muller and T. Deller, Differential regulation of toll-like receptor mRNAs in amyloid plaque-associated brain tissue of aged APP23 transgenic mice, Neurosci Lett 2009;453:41-44.
105. Walter S, Letiembre M, Liu Y, Heine H, Penke B, Hao W, et al. Role of the toll-like receptor 4 in neuroinflammation in Alzheimer’s disease. Cell Physiol Biochem 2007;20:947–956.
106. Jin JJ, Kim HD, Maxwell JA, Li L, Fukuchi K. Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer’s disease. J Neuroinflammation 2008;5:23.
107. Iwahashi M, Yamamura M, Aita T, Okamoto A, Ueno A, Ogawa N, et al. Expression of Toll-like receptor 2 on CD16+ blood monocytes and synovial tissue macrophages in rheumatoid arthritis. Arthritis Rheum. 2004;50(5):1457-67.
108. Sorensen LK, Havemose-Poulsen A, Sonder SU, Bendtzen K, Holmstrup P. Blood cell gene expression profiling in subjects with aggressive periodontitis and chronic arthritis. J Periodontol. 2008;79(3):477-85.
109. Radstake TR, Roelofs MF, Jenniskens YM, Oppers-Walgreen B, van Riel PL, Barrera P, et al. 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. 2004;50(12):3856-65.
110. Roelofs MF, Joosten LA, Abdollahi-Roodsaz S, van Lieshout AW, Sprong T, van den Hoogen FH, et al. 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. 2005;52(8):2313-22.
111. Huang QQ, Sobkoviak R, Jockheck-Clark AR, Shi B, Mandelin AM, Tak PP, et al. Heat shock protein 96 is elevated in rheumatoid arthritis and activates macrophages primarily via TLR2 signaling. J Immunol 2009;182(8):4965-73.
112. Rahman AH, Eisenberg RA. The role of toll-like receptors in systemic lupus erythematosus. Springer Semin Immunopathol. 2006;28(2):131-43.