• 1
    Lipsky PE. Are new agents needed to treat RA? [editorial]. Nat Rev Rheumatol 2009; 5: 5212.
  • 2
    Wolfe F, Mitchell DM, Sibley JT, Fries JF, Bloch DA, Williams CA, et al. The mortality of rheumatoid arthritis. Arthritis Rheum 1994; 37: 48194.
  • 3
    Solomon DH, Karlson EW, Rimm EB, Cannuscio CC, Mandl LA, Manson JE, et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 2003; 107: 13037.
  • 4
    Kremers HM, Crowson CS, Therneau TM, Roger VL, Gabriel SE. High ten-year risk of cardiovascular disease in newly diagnosed rheumatoid arthritis patients: a population-based cohort study. Arthritis Rheum 2008; 58: 226874.
  • 5
    Kumeda Y, Inaba M, Goto H, Nagata M, Henmi Y, Furumitsu Y, et al. Increased thickness of the arterial intima-media detected by ultrasonography in patients with rheumatoid arthritis. Arthritis Rheum 2002; 46: 148997.
  • 6
    Park YB, Ahn CW, Choi HK, Lee SH, In BH, Lee HC, et al. Atherosclerosis in rheumatoid arthritis: morphologic evidence obtained by carotid ultrasound. Arthritis Rheum 2002; 46: 17149.
  • 7
    Warrington KJ, Kent PD, Frye RL, Lymp JF, Kopecky SL, Goronzy JJ, et al. Rheumatoid arthritis is an independent risk factor for multi-vessel coronary artery disease: a case control study. Arthritis Res Ther 2005; 7: R98491.
  • 8
    Chung CP, Oeser A, Avalos I, Gebretsadik T, Shintani A, Raggi P, et al. Utility of the Framingham risk score to predict the presence of coronary atherosclerosis in patients with rheumatoid arthritis. Arthritis Res Ther 2006; 8: R186.
  • 9
    Jacobsson LT, Turesson C, Hanson RL, Pillemer S, Sievers ML, Pettitt DJ, et al. Joint swelling as a predictor of death from cardiovascular disease in a population study of Pima Indians. Arthritis Rheum 2001; 44: 11706.
  • 10
    Choy E, Sattar N. Interpreting lipid levels in the context of high-grade inflammatory states with a focus on rheumatoid arthritis: a challenge to conventional cardiovascular risk actions. Ann Rheum Dis 2009; 68: 4609.
  • 11
    Goodson NJ, Silman AJ, Pattison DJ, Lunt M, Bunn D, Luben R, et al. Traditional cardiovascular risk factors measured prior to the onset of inflammatory polyarthritis. Rheumatology (Oxford) 2004; 43: 7316.
  • 12
    Del Rincon ID, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum 2001; 44: 273745.
  • 13
    Peters MJ, Symmons DP, McCarey D, Dijkmans BA, Nicola P, Kvien TK, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis 2010; 69: 32531.
  • 14
    Full L, Ruisanchez C, Monaco C. The inextricable link between atherosclerosis and prototypical inflammatory diseases rheumatoid arthritis and systemic lupus erythematosus. Arthritis Res Ther 2009; 11: 217.
  • 15
    Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006; 367: 174757.
  • 16
    Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999; 340: 11526.
  • 17
    Aubry MC, Maradit-Kremers H, Reinalda MS, Crowson CS, Edwards WD, Gabriel SE. Differences in atherosclerotic coronary heart disease between subjects with and without rheumatoid arthritis. J Rheumatol 2007; 34: 93742.
  • 18
    Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: part II. Circulation 2003; 108: 17728.
  • 19
    Van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 1994; 89: 3644.
  • 20
    Hansson G. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352: 168595.
  • 21
    Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010; 11: 37384.
  • 22
    Piccinini AM, Midwood KS. DAMPening inflammation by modulating TLR signalling. Mediators Inflamm 2010. E-pub ahead of print.
  • 23
    Jin MS, Lee JO. Structures of the Toll-like receptor family and its ligand complexes. Immunity 2008; 29: 18291.
  • 24
    O'Neill LA. The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress. Immunol Rev 2008; 226: 108.
  • 25
    Chen K, Huang J, Gong W, Iribarren P, Dunlop NM, Wang JM. Toll-like receptors in inflammation, infection and cancer. Int Immunopharmacol 2007; 7: 127185.
  • 26
    Liew FY, Xu D, Brint EK, O'Neill LA. Negative regulation of Toll-like receptor-mediated immune responses. Nat Rev Immunol 2005; 5: 44658.
  • 27
    Mantovani A. Cancer: inflaming metastasis. Nature 2009; 457: 367.
  • 28
    Midwood KS, Piccinini AM, Sacre S. Targeting Toll-like receptors in autoimmunity. Curr Drug Targets 2009; 10: 113955.
  • 29
    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-γ. Arthritis Rheum 2004; 50: 385665.
  • 30
    Sacre SM, Lundberg AM, Andreakos E, Taylor C, Feldmann M, Foxwell BM. Selective use of TRAM in lipopolysaccharide (LPS) and lipoteichoic acid (LTA) induced NF-κB activation and cytokine production in primary human cells: TRAM is an adaptor for LPS and LTA signaling. J Immunol 2007; 178: 214854.
  • 31
    Sacre SM, Andreakos E, Kiriakidis S, Amjadi P, Lundberg A, Giddins G, et al. The Toll-like receptor adaptor proteins MyD88 and Mal/TIRAP contribute to the inflammatory and destructive processes in a human model of rheumatoid arthritis. Am J Pathol 2007; 170: 51825.
  • 32
    Popa C, Abdollahi-Roodsaz S, Joosten LA, Takahashi N, Sprong T, Matera G, et al. Bartonella quintana lipopolysaccharide is a natural antagonist of Toll-like receptor 4. Infect Immun 2007; 75: 48317.
  • 33
    Abdollahi-Roodsaz S, Joosten LA, Roelofs MF, Radstake TR, Matera G, Popa C, et al. Inhibition of Toll-like receptor 4 breaks the inflammatory loop in autoimmune destructive arthritis. Arthritis Rheum 2007; 56: 295767.
  • 34
    Sacre SM, Lo A, Gregory B, Simmonds RE, Williams L, Feldmann M, et al. Inhibitors of TLR8 reduce TNF production from human rheumatoid synovial membrane cultures. J Immunol 2008; 181: 80029.
  • 35
    Brentano F, Kyburz D, Schorr O, Gay R, Gay S. The role of Toll-like receptor signalling in the pathogenesis of arthritis. Cell Immunol 2005; 233: 906.
  • 36
    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: 231322.
  • 37
    Sacre S, Medghalchi M, Gregory B, Brennan F, Williams R. Fluoxetine and citalopram exhibit potent antiinflammatory activity in human and murine models of rheumatoid arthritis and inhibit Toll-like receptors. Arthritis Rheum 2010; 62: 68393.
  • 38
    Deng GM, Nilsson IM, Verdrengh M, Collins LV, Tarkowski A. Intra-articularly localized bacterial DNA containing CpG motifs induces arthritis. Nat Med 1999; 5: 7025.
  • 39
    Cromartie WJ, Craddock JG, Schwab JH, Anderle SK, Yang CH. Arthritis in rats after systemic injection of streptococcal cells or cell walls. J Exp Med 1977; 146: 1585602.
  • 40
    Terato, K., Ye XJ, Miyahara H, Cremer MA, Griffiths MM. Induction by chronic autoimmune arthritis in DBA/1 mice by oral administration of type II collagen and Escherichia coli lipopolysaccharide. Br J Rheumatol 1996; 35: 82838.
  • 41
    Joosten LA, Koenders MI, Smeets RL, Heuvelmans-Jacobs M, Helsen MM, Takeda K, et al. Toll-like receptor 2 pathway drives streptococcal cell wall-induced joint inflammation: critical role of myeloid differentiation factor 88. J Immunol 2003; 171: 614553.
  • 42
    Lee EK, Kang SM, Paik DJ, Kim JM, Youn J. Essential roles of Toll-like receptor-4 signaling in arthritis induced by type II collagen antibody and LPS. Int Immunol 2005; 17: 32533.
  • 43
    Choe JY, Crain B, Wu SR, Corr M. Interleukin 1 receptor dependence of serum transferred arthritis can be circumvented by Toll-like receptor 4 signaling. J Exp Med 2003; 197: 53742.
  • 44
    Abdollahi-Roodsaz S, Joosten LA, Koenders MI, Devesa I, Roelofs MF, Radstake TR, et al. Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis. J Clin Invest 2008; 118: 20516.
  • 45
    Abdollahi-Roodsaz S, Joosten LA, Koenders MI, van den Brand BT, van de Loo FA, van den Berg WB. Local interleukin-1-driven joint pathology is dependent on Toll-like receptor 4 activation. Am J Pathol 2009; 175: 200413.
  • 46
    Pryshchep O, Ma-Krupa W, Younge BR, Goronzy JJ, Weyand CM. Vessel-specific Toll-like receptor profiles in human medium and large arteries. Circulation 2008; 118: 127684.
  • 47
    Erridge C, Burdess A, Jackson AJ, Murray C, Riggio M, Lappin D, et al. Vascular cell responsiveness to Toll-like receptor ligands in carotid atheroma. Eur J Clin Invest 2008; 38: 71320.
  • 48
    Sasu S, LaVerda D, Qureshi N, Golenbock DT, Beasley D. Chlamydia pneumoniae and chlamydial heat shock protein 60 stimulate proliferation of human vascular smooth muscle cells via Toll-like receptor 4 and p44/p42 mitogen-activated protein kinase activation. Circ Res 2001; 89: 24450.
  • 49
    Hong TJ, Ban JE, Choi KH, Son YH, Kim SM, Eo SK, et al. TLR-4 agonistic lipopolysaccharide upregulates interleukin-8 at the transcriptional and post-translational level in vascular smooth muscle cells. Vascul Pharmacol 2009; 50: 349.
  • 50
    Stoll L, Denning GM, Li WG, Rice JB, Harrelson AL, Romig SA. Regulation of endotoxin-induced proinflammatory activation in human coronary artery cells: expression of functional membrane-bound CD14 by human coronary artery smooth muscle cells. J Immunol 2004; 173: 133643.
  • 51
    Yang X, Coriolan D, Murthy V, Schultz K, Golenbock DT, Beasley D. Proinflammatory phenotype of vascular smooth muscle cells: role of efficient Toll-like receptor 4 signaling. Am J Physiol Heart Circ Physiol 2005; 289: H106976.
  • 52
    Yang X, Coriolan D, Schultz K, Golenbock DT, Beasley D. Toll-like receptor 2 mediates persistent chemokine release by Chlamydia pneumoniae-infected vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2005; 25: 230814.
  • 53
    Yang X, Murthy V, Schultz K, Tatro JB, Fitzgerald KA, Beasley D. Toll-like receptor 3 signaling evokes a proinflammatory and proliferative phenotype in human vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 2006; 291: H233443.
  • 54
    Edfeldt K, Swedenborg J, Hansson GK, Yan ZQ. Expression of Toll-like receptors in human atherosclerotic lesions: a possible pathway for plaque activation. Circulation 2002; 105: 115861.
  • 55
    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: 31038.
  • 56
    Otsui K, Inoue N, Kobayashi S, Shiraki R, Honjo T, Takahashi M, et al. Enhanced expression of TLR4 in smooth muscle cells in human atherosclerotic coronary arteries. Heart Vessels 2007; 22: 41622.
  • 57
    Vink A, Schoneveld AH, van der Meer JJ, van Middelaar BJ, Sluijter JP, Smeets MB, et al. In vivo evidence for a role of Toll-like receptor 4 in the development of intimal lesions. Circulation 2002; 106: 198590.
  • 58
    Geng H, 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. Clin Exp Immunol 2006; 143: 26973.
  • 59
    Methe H, Kim JO, Kofler S, Weis M, Nabauer M, Koglin J. Expansion of circulating Toll-like receptor 4-positive monocytes in patients with acute coronary syndrome. Circulation 2005; 111: 265461.
  • 60
    Shiraki R, Inoue N, Kobayashi S, Ejiri J, Otsui K, Honjo T, et al. Toll-like receptor 4 expressions on peripheral blood monocytes were enhanced in coronary artery disease even in patients with low C-reactive protein. Life Sci 2006; 80: 5966.
  • 61
    Kuwahata S, Fujita S, Orihara K, 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 2009; 209: 24854.
  • 62
    Ashida K, Miyazaki K, Takayama E, Tsujimoto H, Ayaori M, Yakushiji T, et al. Characterization of the expression of TLR2 (Toll-like receptor 2) and TLR4 on circulating monocytes in coronary artery disease. J Atheroscler Thromb 2005; 12: 5360.
  • 63
    Liuzzo G, Angiolillo DJ, Buffon A, Rizzello V, Colizzi C, Ginnetti F, et al. Enhanced response of blood monocytes to in vitro lipopolysaccharide-challenge in patients with recurrent unstable angina. Circulation 2001; 103: 223641.
  • 64
    Versteeg D, Hoefer IE, Schoneveld AH, de Kleijn DP, Busser E, Strijder C, et al. Monocyte Toll-like receptor 2 and 4 responses and expression following percutaneous coronary intervention: association with lesion stenosis and fractional flow reserve. Heart 2008; 94: 7706.
  • 65
    Monaco C, Gregan SM, Navin TJ, Foxwell BM, Davies AH, Feldmann M. Toll-like receptor-2 mediates inflammation and matrix degradation in human atherosclerosis. Circulation 2009; 120: 24629.
  • 66
    Mullick AE, Soldau K, Kiosses WB, Bell TA 3rd, Tobias PS, Curtiss LK. Increased endothelial expression of Toll-like receptor 2 at sites of disturbed blood flow exacerbates early atherogenic events. J Exp Med 2008; 205: 37383.
  • 67
    Schoneveld A, Hoefer I, Sluijter JP, Laman JD, de Kleijn DP, Pasterkamp G. Atherosclerotic lesion development and Toll like receptor 2 and 4 responsiveness. Atherosclerosis 2008; 197: 95104.
  • 68
    Bjorkbacka H, Kunjathoor VV, Moore KJ, Koehn S, Ordija CM, Lee MA, et al. Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nat Med 2004; 10: 41621.
  • 69
    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 USA 2004; 101: 1067984.
  • 70
    Mullick AE, Tobias PS, Curtiss LK. Modulation of atherosclerosis in mice by Toll-like receptor 2. J Clin Invest 2005; 115: 314956.
  • 71
    Madan M, Amar S. Toll-like receptor-2 mediates diet and/or pathogen associated atherosclerosis: proteomic findings. PLoS One 2008; 3: e3204.
  • 72
    Liu X, Ukai T, Yumoto H, Davey M, Goswami S, Gibson FC 3rd, et al. Toll-like receptor 2 plays a critical role in the progression of atherosclerosis that is independent of dietary lipids. Atherosclerosis 2008; 196: 14654.
  • 73
    Ishida BY, Blanche PJ, Nichols AV, Yashar M, Paigen B. Effects of atherogenic diet consumption on lipoproteins in mouse strains C57BL/6 and C3H. J Lipid Res 1991; 32: 55968.
  • 74
    Nishina P, Wang J, Toyofuku W, Kuypers FA, Ishida BY, Paigen B. Atherosclerosis and plasma and liver lipids in nine inbred strains of mice. Lipids 1993; 28: 599605.
  • 75
    Wright SD, Burton C, Hernandez M, Hassing H, Montenegro J, Mundt S, et al. Infectious agents are not necessary for murine atherogenesis. J Exp Med 2000; 191: 143742.
  • 76
    Schoneveld AH, Oude Nijhuis MM, van Middelaar B, Laman JD, de Kleijn DP, Pasterkamp G. Toll-like receptor 2 stimulation induces intimal hyperplasia and atherosclerotic lesion development. Cardiovasc Res 2005; 66: 1629.
  • 77
    Funk JL, Feingold KR, Moser AH, Grunfeld C. Lipopolysaccharide stimulation of RAW 264.7 macrophages induces lipid accumulation and foam cell formation. Atherosclerosis 1993; 98: 6782.
  • 78
    Kim S, Takahashi H, Lin WW, Descargues P, Grivennikov S, Kim Y, et al. Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 2009; 457: 1026.
  • 79
    Lee JG, Lim EJ, Park DW, Lee SH, Kim JR, Baek SH. A combination of Lox-1 and Nox1 regulates TLR9-mediated foam cell formation. Cell Signal 2008; 20: 226675.
  • 80
    Oiknine J, Aviram M. Increased susceptibility to activation and increased uptake of low density lipoprotein by cholesterol-loaded macrophages. Arterioscler Thromb 1992; 12: 74553.
  • 81
    Choi S, Harkewicz R, Lee JH, Boullier A, Almazan F, Li AC, et al. Lipoprotein accumulation in macrophages via Toll-like receptor-4-dependent fluid phase uptake. Circ Res 2009; 104: 135563.
  • 82
    Cao F, Castrillo A, Tontonoz P, Re F, Byrne GI. Chlamydia pneumoniae-induced macrophage foam cell formation is mediated by Toll-like receptor 2. Infect Immun 2007; 75: 7539.
  • 83
    Chen S, Sorrentino R, Shimada K, Bulut Y, Doherty TM, Crother TR. Chlamydia pneumoniae-induced foam cell formation requires MyD88-dependent and -independent signaling and is reciprocally modulated by liver X receptor activation. J Immunol 2008; 181: 718693.
  • 84
    Naiki Y, Sorrentino R, Wong MH, Michelsen KS, Shimada K, Chen S, et al. TLR/MyD88 and liver X receptor α signaling pathways reciprocally control Chlamydia pneumoniae-induced acceleration of atherosclerosis. J Immunol 2008; 181: 717685.
  • 85
    Doyle S, O'Connell RM, Miranda GA, Vaidya SA, Chow EK, Liu PT, et al. Toll-like receptors induce a phagocytic gene program through p38. J Exp Med 2004; 199: 8190.
  • 86
    Castrillo A, Joseph SB, Vaidya SA, Haberland M, Fogelman AM, Cheng G, et al. Crosstalk between LXR and Toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism. Mol Cell 2003; 12: 80516.
  • 87
    Yvan-Charvet L, Welch C, Pagler TA, Ranalletta M, Lamkanfi M, Han S, et al. Increased inflammatory gene expression in ABC transporter-deficient macrophages: free cholesterol accumulation, increased signaling via Toll-like receptors, and neutrophil infiltration of atherosclerotic lesions. Circulation 2008; 118: 183747.
  • 88
    Shinohara M, Hirata K, Yamashita T, Takaya T, Sasaki N, Shiraki R, et al. Local overexpression of Toll-like receptors at the vessel wall induces atherosclerotic lesion formation: synergism of TLR2 and TLR4. Arterioscler Thromb Vasc Biol 2007; 27: 238491.
  • 89
    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: 301525.
  • 90
    Tsukumo DM, Carvalho-Filho MA, Carvalheira JB, Prada PO, Hirabara SM, Schenka AA, et al. Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes 2007; 56: 198698.
  • 91
    Lin Y, Lee H, Berg AH, Lisanti MP, Shapiro L, Scherer PE. The lipopolysaccharide-activated Toll-like receptor (TLR)-4 induces synthesis of the closely related receptor TLR-2 in adipocytes. J Biol Chem 2000; 275: 2425563.
  • 92
    Roncon-Albuquerque R Jr, Moreira-Rodrigues M, Faria B, Ferreira AP, Cerqueira C, Lourenco AP, et al. Attenuation of the cardiovascular and metabolic complications of obesity in CD14 knockout mice. Life Sci 2008; 83: 50210.
  • 93
    Vijay-Kumar M, Aitken JD, Carvalho FA, Cullender TC, Mwangi S, Srinivasan S, et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 2010; 328: 22831.
  • 94
    Hosoi T, Yokoyama S, Matsuo S, Akira S, Ozawa K. Myeloid differentiation factor 88 (MyD88)-deficiency increases risk of diabetes in mice. PLoS One 2010; 5: e12537.
  • 95
    Miller YI, Viriyakosol S, Binder CJ, Feramisco JR, Kirkland TN, Witztum JL. Minimally modified LDL binds to CD14, induces macrophage spreading via TLR4/MD-2, and inhibits phagocytosis of apoptotic cells. J Biol Chem 2003; 278: 15618.
  • 96
    Bae YS, Lee JH, Choi SH, Kim S, Almazan F, Witztum JL, et al. Macrophages generate reactive oxygen species in response to minimally oxidized low-density lipoprotein: Toll-like receptor 4- and spleen tyrosine kinase-dependent activation of NADPH oxidase 2. Circ Res 2009; 104: 2108.
  • 97
    Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 2010; 11: 15561.
  • 98
    Kawakami A, Osaka M, Aikawa M, Uematsu S, Akira S, Libby P, et al. Toll-like receptor 2 mediates apolipoprotein CIII-induced monocyte activation. Circ Res 2008; 103: 14029.
  • 99
    Erridge C, Samani NJ. Saturated fatty acids do not directly stimulate Toll-like receptor signaling. Arterioscler Thromb Vasc Biol 2009; 29: 19449.
  • 100
    O'Brien KD, McDonald TO, Kunjathoor V, Eng K, Knopp EA, Lewis K, et al. Serum amyloid A and lipoprotein retention in murine models of atherosclerosis. Arterioscler Thromb Vasc Biol 2005; 25: 78590.
  • 101
    Cheng N, He R, Tian J, Ye PP, Ye RD. Cutting edge: TLR2 is a functional receptor for acute-phase serum amyloid A. J Immunol 2008; 181: 226.
  • 102
    Smiley ST, King JA, Hancock WW. Fibrinogen stimulates macrophage chemokine secretion through Toll-like receptor 4. J Immunol 2001; 167: 288794.
  • 103
    Dvorak HF, Senger DR, Dvorak AM, Harvey VS, McDonagh J. Regulation of extravascular coagulation by microvascular permeability. Science 1985; 227: 105961.
  • 104
    Scott DL, Delamere JP, Walton KW. The distribution of fibronectin in the pannus in rheumatoid arthritis. Br J Exp Pathol 1981; 62: 3628.
  • 105
    Van Keulen JK, de Kleijn DP, Nijhuis MM, Busser E, Velema E, Fijnheer R, et al. Levels of extra domain A containing fibronectin in human atherosclerotic plaques are associated with a stable plaque phenotype. Atherosclerosis 2007; 195: e8391.
  • 106
    Gondokaryono SP, Ushio H, Niyonsaba F, Hara M, Takenaka H, Jayawardana ST, et al. The extra domain A of fibronectin stimulates murine mast cells via Toll-like receptor 4. J Leukoc Biol 2007; 82: 65765.
  • 107
    Midwood KS, Orend G. The role of tenascin-C in tissue injury and tumorigenesis. J Cell Commun Signal 2009; 3: 287310.
  • 108
    Goh FG, Piccinini AM, Krausgruber T, Udalova IA, Midwood KS. Transcriptional regulation of the endogenous danger signal tenascin-C: a novel autocrine loop in inflammation. J Immunol 2010; 184: 265562.
  • 109
    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. Nat Med 2009; 15: 77480.
  • 110
    Wallner K, Li C, Shah PK, Fishbein MC, Forrester JS, Kaul S, et al. Tenascin-C is expressed in macrophage-rich human coronary atherosclerotic plaque. Circulation 1999; 99: 12849.
  • 111
    Schaefer L, Babelova A, Kiss E, Hausser HJ, Baliova M, Krzyzankova M, et al. The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages. J Clin Invest 2005; 115: 222333.
  • 112
    Cs-Szabo G, Roughley PJ, Plaas AH, Glant TT. Large and small proteoglycans of osteoarthritic and rheumatoid articular cartilage. Arthritis Rheum 1995; 38: 6608.
  • 113
    Polgar A, Falus A, Koo E, Ujfalussy I, Sesztak M, Szuts I, et al. Elevated levels of synovial fluid antibodies reactive with the small proteoglycans biglycan and decorin in patients with rheumatoid arthritis or other joint diseases. Rheumatology (Oxford) 2003; 42: 5227.
  • 114
    O'Brien KD, Lewis K, Fischer JW, Johnson P, Hwang JY, Knopp EA, et al. Smooth muscle cell biglycan overexpression results in increased lipoprotein retention on extracellular matrix: implications for the retention of lipoproteins in atherosclerosis. Atherosclerosis 2004; 177: 2935.
  • 115
    Seidelmann SB, Kuo C, Pleskac N, Molina J, Sayers S, Li R, et al. Athsq1 is an atherosclerosis modifier locus with dramatic effects on lesion area and prominent accumulation of versican. Arterioscler Thromb Vasc Biol 2008; 28: 21806.
  • 116
    Tran-Lundmark K, Tran PK, Paulsson-Berne G, Friden V, Soininen R, Tryggvason K, et al. Heparan sulfate in perlecan promotes mouse atherosclerosis: roles in lipid permeability, lipid retention, and smooth muscle cell proliferation. Circ Res 2008; 103: 4352.
  • 117
    Kunjathoor VV, Chiu DS, O'Brien KD, LeBoeuf RC. Accumulation of biglycan and perlecan, but not versican, in lesions of murine models of atherosclerosis. Arterioscler Thromb Vasc Biol 2002; 22: 4628.
  • 118
    Witter J, Roughley PJ, Webber C, Roberts N, Keystone E, Poole AR. The immunologic detection and characterization of cartilage proteoglycan degradation products in synovial fluids of patients with arthritis. Arthritis Rheum 1987; 30: 51929.
  • 119
    Scheibner KA, Lutz MA, Boodoo S, Fenton MJ, Powell JD, Horton MR. Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J Immunol 2006; 177: 127281.
  • 120
    Taylor K, Trowbridge JM, Rudisill JA, Termeer CC, Simon JC, Gallo RL. Hyaluronan fragments stimulate endothelial recognition of injury through TLR4. J Biol Chem 2004; 279: 1707984.
  • 121
    Termeer C, Benedix F, Sleeman J, Fieber C, Voith U, Ahrens T, et al. Oligosaccharides of hyaluronan activate dendritic cells via Toll-like receptor 4. J Exp Med 2002; 195: 99111.
  • 122
    Chai S, Chai Q, Danielsen CC, Hjorth P, Nyengaard JR, Ledet T, et al. Overexpression of hyaluronan in the tunica media promotes the development of atherosclerosis. Circ Res 2005; 96: 58391.
  • 123
    Taniguchi N, Kawahara K, Yone K, Hashiguchi T, Yamakuchi M, Goto M, et al. High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine. Arthritis Rheum 2003; 48: 97181.
  • 124
    Pullerits R, Jonsson IM, Verdrengh M, Bokarewa M, Andersson U, Erlandsson-Harris H, et al. High mobility group box chromosomal protein 1, a DNA binding cytokine, induces arthritis. Arthritis Rheum 2003; 48: 1693700.
  • 125
    Porto A, Palumbo R, Pieroni M, Aprigliano G, Chiesa R, Sanvito F, et al. Smooth muscle cells in human atherosclerotic plaques secrete and proliferate in response to high mobility group box 1 protein. FASEB J 2006; 20: 25656.
  • 126
    Degryse B, Bonaldi T, Scaffidi P, Muller S, Resnati M, Sanvito F, et al. The high mobility group (HMG) boxes of the nuclear protein HMG1 induce chemotaxis and cytoskeleton reorganization in rat smooth muscle cells. J Cell Biol 2001; 152: 1197206.
  • 127
    Harja E, Bu DX, Hudson BI, Chang JS, Shen X, Hallam K, et al. Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE-/- mice. J Clin Invest 2008; 118: 18394.
  • 128
    Roelofs MF, Abdollahi-Roodsaz S, Joosten LA, van den Berg WB, Radstake TR. The orchestra of Toll-like receptors and their potential role in frequently occurring rheumatic conditions. Arthritis Rheum 2008; 58: 33848.
  • 129
    Bacon PA, Stevens RJ, Carruthers DM, Young SP, Kitas GD. Accelerated atherogenesis in autoimmune rheumatic diseases. Autoimmun Rev 2002; 1: 33847.
  • 130
    Turesson C, McClelland RL, Christianson TJ, Matteson EL. Severe extra-articular disease manifestations are associated with an increased risk of first ever cardiovascular events in patients with rheumatoid arthritis. Ann Rheum Dis 2007; 66: 705.
  • 131
    Van Doornum S, McColl G, Wicks IP. Tumour necrosis factor antagonists improve disease activity but not arterial stiffness in rheumatoid arthritis. Rheumatology (Oxford) 2005; 44: 142832.
  • 132
    Del Porto F, Lagana B, Lai S, Nofroni I, Tinti F, Vitale M, et al. Response to anti-tumour necrosis factor α blockade is associated with reduction of carotid intima-media thickness in patients with active rheumatoid arthritis. Rheumatology (Oxford) 2007; 46: 11115.
  • 133
    Jacobsson LT, Turesson C, Gulfe A, Kapetanovic MC, Petersson IF, Saxne T, et al. Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis. J Rheumatol 2005; 32: 12138.
  • 134
    Dixon WG, Watson KD, Lunt M, Hyrich KL, British Society for Rheumatology Biologics Register Control Centre Consortium, Silman AJ, et al. Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti–tumor necrosis factor α therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum 2007; 56: 290512.
  • 135
    Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 2002; 359: 11737.
  • 136
    Jain MK, Ridker PM. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat Rev Drug Discov 2005; 4: 97787.
  • 137
    O'Driscoll G, Green D, Taylor RR. Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation 1997; 95: 112631.
  • 138
    Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000; 6: 1399402.
  • 139
    Okamoto H, Koizumi K, Kamitsuji S, Inoue E, Hara M, Tomatsu T, et al. Beneficial action of statins in patients with rheumatoid arthritis in a large observational cohort. J Rheumatol 2007; 34: 9648.
  • 140
    Toms TE, Panoulas VF, Douglas KM, Griffiths H, Sattar N, Smith JP, et al. Statin use in rheumatoid arthritis in relation to actual cardiovascular risk: evidence for substantial undertreatment of lipid-associated cardiovascular risk? Ann Rheum Dis 2009; 69: 6838.
  • 141
    Ridker PM. Testing the inflammatory hypothesis of atherothrombosis: scientific rationale for the cardiovascular inflammation reduction trial (CIRT). J Thromb Haemost 2009; 7 Suppl 1: 3329.
  • 142
    Hennessy EJ, Parker AE, O'Neill LA. Targeting Toll-like receptors: emerging therapeutics? Nat Rev Drug Discov 2010; 9: 293307.
  • 143
    Vanags D, Williams B, Johnson B, Hall S, Nash P, Taylor A, et al. Therapeutic efficacy and safety of chaperonin 10 in patients with rheumatoid arthritis: a double-blind randomised trial. Lancet 2006; 368: 85563.
  • 144
    Dong L, Ito S, Ishii KJ, Klinman DM. Suppressive oligonucleotides protect against collagen-induced arthritis in mice. Arthritis Rheum 2004; 50: 16869.
  • 145
    Zeuner RA, Ishii KJ, Lizak MJ, Gursel I, Yamada H, Klinman DM, et al. Reduction of CpG-induced arthritis by suppressive oligodeoxynucleotides. Arthritis Rheum 2002; 46: 221924.
  • 146
    Kokkola R, Li J, Sundberg E, Aveberger AC, Palmblad K, Yang H, et al. Successful treatment of collagen-induced arthritis in mice and rats by targeting extracellular high mobility group box chromosomal protein 1 activity. Arthritis Rheum 2003; 48: 20528.
  • 147
    Andersson U, Tracey KJ. HMGB1 as a mediator of necrosis-induced inflammation and a therapeutic target in arthritis. Rheum Dis Clin North Am 2004; 30: 62737, xi.
  • 148
    Pisetsky DS, Erlandsson-Harris H, Andersson U. High-mobility group box protein 1 (HMGB1): an alarmin mediating the pathogenesis of rheumatic disease. Arthritis Res Ther 2008; 10: 209.
  • 149
    Rice JW, Veal JM, Fadden RP, Barabasz AF, Partridge JM, Barta TE, et al. Small molecule inhibitors of Hsp90 potently affect inflammatory disease pathways and exhibit activity in models of rheumatoid arthritis. Arthritis Rheum 2008; 58: 376575.
  • 150
    Kakimoto K, Matsukawa A, Yoshinaga M, Nakamura H. Suppressive effect of a neutrophil elastase inhibitor on the development of collagen-induced arthritis. Cell Immunol 1995; 165: 2632.
  • 151
    Arslan F, Smeets MB, O'Neill LA, Keogh B, McGuirk P, Timmers L, et al. Myocardial ischemia/reperfusion injury is mediated by leukocytic Toll-like receptor-2 and reduced by systemic administration of a novel anti-Toll-like receptor-2 antibody. Circulation 2010; 121: 8090.