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• W2003013587 abstract "Atherosclerosis is inflammation of the vessel wall of the arterial tree. This inflammation arises at specific areas that experience disturbed blood flow such as bifurcations and the lesser curvature of the aortic arch. Although all endothelial cells are exposed to comparable levels of circulating plasma cholesterol, only endothelial cells overlaying lesions display an inflamed phenotype. This occurs even in the absence of any additional exacerbating disease factors because blood flow controls the expression of Toll-like receptors (TLR), which are initiators of cellular activation and inflammation. TLR2- and 4-expression exert an overall proatherogenic effect in hyperlipidemic mice. TLR activation of the endothelium promotes lipid accumulation and leukocyte accumulation within lesions. Atherosclerosis is inflammation of the vessel wall of the arterial tree. This inflammation arises at specific areas that experience disturbed blood flow such as bifurcations and the lesser curvature of the aortic arch. Although all endothelial cells are exposed to comparable levels of circulating plasma cholesterol, only endothelial cells overlaying lesions display an inflamed phenotype. This occurs even in the absence of any additional exacerbating disease factors because blood flow controls the expression of Toll-like receptors (TLR), which are initiators of cellular activation and inflammation. TLR2- and 4-expression exert an overall proatherogenic effect in hyperlipidemic mice. TLR activation of the endothelium promotes lipid accumulation and leukocyte accumulation within lesions. Atherosclerosis was once thought to be a simple lipid storage disease that caused pathology by arterial obstruction. The pathology leads to arterial obstruction, but not simply by accumulation of lipid. Atherosclerotic lesions are foci of vessel wall inflammation (1Michelsen K.S. Doherty T.M. Shah P.K. Arditi M. TLR signaling: an emerging bridge from innate immunity to atherogenesis.J. Immunol. 2004; 173: 5901-5907Crossref PubMed Scopus (194) Google Scholar, 2Ross R. Atherosclerosis–an inflammatory disease.N. Engl. J. Med. 1999; 340: 115-126Crossref PubMed Scopus (19278) Google Scholar, 3Blankenberg S. Yusuf S. The inflammatory hypothesis: any progress in risk stratification and therapeutic targets.Circulation. 2006; 114: 1557-1560Crossref PubMed Scopus (24) Google Scholar). Many hallmarks of inflammation are present and include the expression of soluble inflammatory mediators. Leukocytes, including macrophages, dendritic cells, and lymphocytes, accumulate at lesion sites and the overlying endothelial cells display an inflamed phenotype. Systemically, acute phase proteins are elevated, such as serum amyloid A in mice and C-reactive protein in humans. Lesions begin early as fatty streaks and progress to pathologic lesions under the influence of both genetic and lifestyle insults (4Zieske A.W. Malcom G.T. Strong J.P. Natural history and risk factors of atherosclerosis in children and youth: the PDAY study.Pediatr. Pathol. Mol. Med. 2002; 21: 213-237Crossref PubMed Scopus (164) Google Scholar). Whereas most plaques are the result of many years of gradual asymptomatic disease progression, the final obstructive event is a sudden thrombotic event. During the major part of a lifetime that will elapse between fatty streak formation and overt disease, multiple events will occur to accelerate lesion progression. Genetic diseases like diabetes, hypertension, and notably, hypercholesterolemias lead to severe disease (5Soutar A.K. Naoumova R.P. Mechanisms of disease: genetic causes of familial hypercholesterolemia.Nat. Clin. Pract. Cardiovasc. Med. 2007; 4: 214-225Crossref PubMed Scopus (458) Google Scholar). Lifestyle choices including smoking, obesity, and a sedentary lifestyle also will accelerate disease progression. Appreciating that a major component of atherosclerosis is chronic inflammation raises many questions about the relationship between inflammatory processes and disease severity. Inflammation is a normal homeostatic response of the body to wounds or infections. Upon resolution of the problem, inflammation is self limiting and homeostasis is restored. Chronic inflammation occurs when inflammatory responses cannot resolve the problem or when self-limiting mechanisms go awry (6Nathan C. Points of control in inflammation.Nature. 2002; 420: 846-852Crossref PubMed Scopus (2027) Google Scholar). We know some of the factors that contribute to disease progression, including hyperlipidemia, lipid oxidation, leukocyte accumulation into the arterial wall, and foam cell formation. Inflammatory diseases elsewhere in the body, ranging from periodontitis to autoimmune diseases like lupus, can also have an exacerbating influence on lesion progression (7Van Doornum S. McColl G. Wicks P. Accelerated atherosclerosis: an extraarticular feature of rheumatoid arthritis.Arthritis Rheum. 2002; 46: 862-873Crossref PubMed Scopus (570) Google Scholar, 8Hauer A.D. Vos P.De Peterse N. Cate H.ten Berkel Th. J.C. van Stassem F.R.N. Kuiper J. Delivery of Chlamydia pneumoniae to the vessel wall aggravates atherosclerosis in LDLr−/− mice.Cardiovasc. Res. 2006; 69: 280-288Crossref PubMed Scopus (32) Google Scholar, 9Raschi E. Borghi M. Grossi C. Broggini V. Pierangeli S. Meroni P. Toll-like receptors: another player in the pathogenesis of the anti-phospholipid syndrome.Lupus. 2008; 17: 937-942Crossref PubMed Scopus (57) Google Scholar). Notably, the factors that promote atherosclerosis do not do so uniformly throughout the arterial tree. Site-specific plaque development is the result of disturbed hydrodynamic blood flow (10Wasserman S.M. Topper J.N. Adaption of the endothelium to fluid flow: in vitro analyses of gene expression and in vivo implications.Vasc. Med. 2004; 9: 35-45Crossref PubMed Scopus (73) Google Scholar). Regions of the arterial tree exposed to laminar flow are protected from endothelial activation and atherosclerosis. This antiinflammatory activity is mediated by mitogen-activated protein kinase phosphatase (MKP-1), a negative regulator of p38 and c-Jun N-terminal kinase (11Zakkar M. Chaudhury H. Sandvik G. Enesa K. Luong L.A. Cuhlmann S. Mason J.C. Krams R. Clark A.R. Haskard D.O. al et Increased endothelial mitogen-activated protein kinase phosphatase-1 expression suppresses proinflammatory activation at sites that are resistant to atherosclerosis.Circ. Res. 2008; 103: 726-732Crossref PubMed Scopus (92) Google Scholar). Lesion susceptible sites are vessel bifurcations and the lesser curvature of the aortic arch. These sites display an inflamed phenotype even in the absence of any additional exacerbating disease factors (12Matharu N.M. Rainger G.E. Vohra R. Nash G.B. Effects of disturbed flow on endothelial cell function: pathogenic implications of modified leukocyte recruitment.Biorheology. 2006; 43: 31-44PubMed Google Scholar, 13Dai G. Natarajan M.R. Kaazempur-Mofrad, S. Zhang Y. Vaughn S. Blackman B.R. Kamm R.D. Gimbrone Jr., G.Garcia-Cardena, and M.A. Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and -resistant regions of human vasculature.Proc. Natl. Acad. Sci. USA. 2004; 101: 14871-14876Crossref PubMed Scopus (522) Google Scholar, 14Feintuch A. Ruengsakulrach P. Lin A. Zhang J. Zhou Y-Q. Bishop J. Davidson L. Courtman D. Foster F.S. Steinman D.A. al et Hemodynamics in the mouse aortic arch as assessed by MRI, ultrasound, and numberical modeling.Am. J. Physiol. Heart Circ. Physiol. 2007; 292: H884-H892Crossref PubMed Scopus (99) Google Scholar). The biochemical mechanisms that enable endothelial cells to detect flow patterns are beginning to be understood (15Tzima E. Kiosses M.Irani-Tehrani, W.B. Dejana E. Schultz D.A. Engelhardt B. Cao G. DeLisser H. Schwartz M.A. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress.Nature. 2005; 437: 426-431Crossref PubMed Scopus (1270) Google Scholar, 16Parmar K.M. Larman H.B. Dia G. Zhang Y. Wang E.T. Moorthy S.N. Kratz J.R. Lin Z. Jain M.K. Gimbrone Jr., M.A. al et Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2.J. Clin. Invest. 2006; 116: 49-58Crossref PubMed Scopus (531) Google Scholar, 17Dai G. Vaughn S. Zhang Y. Wang E.T. Gimbrone Jr., G.Garcia-Cardena, and M.A. Biomechanical forces in atherosclerosis-resistant vascular regions regulate endothelial redox balance via phosphoinositol 3-kinase/Akt-dependent activation of Nrf2.Circ. Res. 2007; 101: 723-733Crossref PubMed Scopus (193) Google Scholar). Arterial endothelial cells possess a single cilium able to detect the mechanical forces of blood flow (18Hierck B.P. Heiden K.Van der Alkemade F.E. Pas S.Van de Thienen J.V. Van Groenendijk B.C. Bax W.H. Laarse A.Van der Deruiter M.C. Horrevoets A.J. al et Primary cilia sensitize endothelial cells for fluid shear stress.Dev. Dyn. 2008; 237: 725-735Crossref PubMed Scopus (137) Google Scholar, 19Poelmann R.E. Heiden K.Van der Groot A.Gittenberger-de Hierck B.P. Deciphering the endothelial shear stress sensor.Circulation. 2008; 117: 1124-1126Crossref PubMed Scopus (42) Google Scholar, 20Nauli S.M. Kawanabe Y. Kaminski J.J. Pearce W.J. Ingber D.E. Zhou J. Endothelial cilia are fluid shear sensors that regulate calcium signaling and nitric oxide production through polycystin-1.Circulation. 2008; 117: 1161-1171Crossref PubMed Scopus (347) Google Scholar) that distinguish disturbed flow from laminar flow. This in turn dictates endothelial cell phenotype. Cells at plaque susceptible sites have a proinflammatory phenotype, which is both permissive and causative of plaque development. For example, the proinflammatory endothelial phenotype is permissive in that it allows expression of proinflammatory receptors such as Toll-like receptors (TLRs) and causative in that it permits expression of cell surface adhesion molecules (such as vascular cell adhesion molecule-1), which foster inflammatory leukocyte accumulation into the intima (21Partridge J. Carlsen H. Enesa K. Chaudhury H. Zakkar M. Luong L. Kinderlerer A. Johns M. Blomhoff R. Mason J.C. al et Laminar shear stress acts as a switch to regulate divergent functions of NF-kappaB in endothelial cells.FASEB J. 2007; 21: 3553-3561Crossref PubMed Scopus (114) Google Scholar, 22Suo J. Ferrara D.E. Sorescu D. Guldberg R.E. Taylor W.R. Giddens D.P. Hemodynamic shear stresses in mouse aortas; implications for atherogenesis.Arterioscler. Thromb. Vasc. Biol. 2006; 27: 346-351Crossref PubMed Scopus (248) Google Scholar, 23Mullick A.E. Soldau K. Kiosses W.B. Tobias P.S. Bell T.A. Curtiss L.K. Increased endothelial expression of Toll-like receptor 2 at sites of disturbed blood flow exacerbates early atherogenic events.J. Exp. Med. 2008; 205: 373-383Crossref PubMed Scopus (181) Google Scholar). No specific disease risk has been identified that would promote a proinflammatory phenotype only at arterial bifurcations and the lesser curvature of the aortic arch. TLRs expressed by endothelial cells may provide a clue to this conundrum. If inflammation is a hallmark of atherosclerosis, the role of TLRs must be understood because they initiate inflammation. They do so every day and the majority of these responses are beneficial by promoting healing and homeostasis. However, occasionally these responses go awry and cause pathology. For example, if a TLR2- or TLR4-mediated innate immune response to infection does not develop in time to curb microbial growth, the host dies of bacteremia (24Akira S. Takeda K. Functions of toll-like receptors: lessons from KO mice.C. R. Biol. 2004; 327: 581-589Crossref PubMed Scopus (159) Google Scholar). Atherosclerosis is one of these pathologic consequences. TLR2 promotes atherosclerosis progression. Hypercholesterolemic LDLr−/− mice with a total deficiency of TLR2 have only minimal lesions (25Mullick A.E. Tobias P.S. Curtiss L.K. Modulation of atherosclerosis in mice by Toll-like Receptor 2.J. Clin. Invest. 2005; 115: 3149-3156Crossref PubMed Scopus (465) Google Scholar). Liu et al. (26Liu X. Ukai T. Yumoto H. Davey M. Goswami S. III F.C. Gibson Genco C.A. Toll-like receptor 2 plays a critical role in the progression of atherosclerosis that is independent of dietary lipids.Atherosclerosis. 2008; 196: 146-154Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar) recently confirmed the same influence of a TLR2-deficiency in apoE−/− mice and Madan (27Madan M. Amar A. Toll-like receptor-2 mediates diet and/or pathogen associated atherosclerosis: proteomic findings.PLoS ONE. 2008; 3: e3204Crossref PubMed Scopus (84) Google Scholar) observed a similar level of disease protection in apoE+/− mice. So far, only TLR4 and TLR2 have been studied in mouse models of disease to determine their role in atherogenesis. However, the innate immune system employs a number of pattern recognition receptor families to respond to DNAs and RNAs, either from invading microbes or within the host. One could easily make the case that other TLRs, especially TLR3, TLR7, and TLR9, should be examined because they also initiate important inflammatory responses (28Lee J.G. Lim E.J. Park D.W. Lee S.H. Kim J.R. Baek S.H. A combination of Lox-1 and Nox1 regulates TLR9-mediated foam cell formation.Cell. Signal. 2008; Crossref Scopus (73) Google Scholar). In lesions, macrophages, dendritic cells, endothelial cells, and vascular smooth muscle cells can all express TLR2 and TLR4 (29Akashi S. Shimazu R. Ogata H. Nagai Y. Takeda K. Kimoto M. Miyake K. Cutting edge: cell surface expression and lipopolysaccharide signaling via the toll-like receptor 4-MD-2 complex on mouse peritoneal macrophages.J. Immunol. 2000; 164: 3471-3475Crossref PubMed Scopus (423) Google Scholar, 30Biragyn A. Ruffini P.A. Leifer C.A. Klyushnenkova E. Shakhov A. Chertov O. Shirakawa A.K. Farber J.M. Segal D.M. Oppenheim J. Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2.Science. 2002; 298: 1025-1029Crossref PubMed Scopus (816) Google Scholar, 31Chen S. Wong M.H. Schulte D.J. Arditi M. Michelsen K.S. Differential expression of toll-like receptor 2 (TLR2) and responses to TLR2 ligands between human and murine vascular endothelial cells.J. Endotoxin Res. 2007; 13: 281-296Crossref PubMed Scopus (39) Google Scholar). Importantly, although essentially all cells in lesions can express TLRs, this expression is not constitutive. TLR expression is regulated by multiple factors including cell differentiation and the presence of their cognate ligands. TLR4 signals through the myeloid differentiation factor 88 (MyD88) (as does TLR2) as well as through the Toll/IL-1 receptor domain-related adaptor protein that induces interferon (TRIF). Our laboratory is examining the effect of a TRIF-deficiency on atherosclerosis in LDLr−/− mice, and others demonstrated that MyD88 participates in atherogenesis. MyD88 deficiency leads to reductions in plaque size, lipid content, expression of proinflammatory genes, cytokines, and chemokines such as IL-12 and monocyte chemoattractant protein-1 (32Michelsen K.S. Wong M.H. Shah P.K. Zhang W. Yano J. Doherty T.M. Akira S. Rajavashisth T.B. Arditi M. 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: 10679-10684Crossref PubMed Scopus (874) Google Scholar). However, MyD88 is also involved with signaling originating from the IL-1 family of receptors. Because IL-1 and IL-18 are proatherogenic, these effects of a MyD88 deficiency on lesion formation are not sufficient, although necessary, to implicate TLRs in atherosclerosis. An early study reported that C3H/HeJ mice compared with C57BL/6 mice are resistant to atherosclerosis when they are fed a high cholesterol diet (33Paigen B. Genetics of responsiveness to high-fat and high-cholesterol diets in the mouse.Am. J. Clin. Nutr. 1995; 62: 458S-462SCrossref PubMed Scopus (132) Google Scholar). These C3H/HeJ mice carry a point mutation in the intracytoplasmic region of TLR4 that codes for a nonfunctional receptor. Leukocytes from C3H/HeJ mice lack inflammatory responses to minimally modified LDL, supporting the idea that minimally modified LDL initiates atherosclerosis via TLR4 (34Shi W.B. Haberland M.E. Jien M.L. Shih D.M. Lusis A.J. Endothelial responses to oxidized lipoproteins determine genetic susceptibility to atherosclerosis in mice.Circulation. 2000; 102: 75-81Crossref PubMed Scopus (161) Google Scholar). However, transfer of bone marrow-derived cells from an atherosclerosis-prone mouse strain into C3H/HeJ mice does not reverse the phenotype of the C3H/HeJ mice, indicating a key role for endothelial cell TLR4 during early events of atherosclerosis. TLR4 can directly interfere with cholesterol metabolism in macrophages (35Castrillo A. Joseph S.B. Vaidya S.A. Haberland M. Fogelman A.M. Cheng G. Tontonoz P. Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism.Mol. Cell. 2003; 12: 805-816Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar), suggesting a mechanism by which TLR4 may affect disease pathology. A total deficiency of TLR4 is associated with reductions in lesion size, lipid content, and macrophage infiltration in apoE−/− mice fed a high cholesterol diet for six months (32Michelsen K.S. Wong M.H. Shah P.K. Zhang W. Yano J. Doherty T.M. Akira S. Rajavashisth T.B. Arditi M. 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: 10679-10684Crossref PubMed Scopus (874) Google Scholar). This deficiency in the double mutant mice results in a 25% reduction in the aortic surface area covered by lesions, as well as a reduction in the lipid content of heart aortic sinus lesions. Importantly, this reduction in disease severity is observed without a significant effect of the TLR4 deficiency on plasma cholesterol levels. Hollestelle et al. (36Hollestelle S.C. Vries M.R. De Keulen J.K. Van Schoneveld A.H. Vink A. Strijder C.F. Middelaar B.J. Van Pasterkamp G. Quax P.H. Kleijn D.P. de Toll-like receptor 4 is involved in outward arterial remodeling.Circulation. 2004; 109: 393-398Crossref PubMed Scopus (174) Google Scholar), demonstrated that TLR4 is a vital receptor in arterial remodeling. A femoral artery cuff exposure to lipopolysaccharides in proatherogenic apoE Leiden transgenic mice increased plaque formation and outward arterial remodeling. Endothelial cells lack the adaptor molecule TRIF-related adapter protein that is required for TLR4 signaling in bone marrow-derived macrophages (37Bjo¨rkbacka H. Multiple roles of Toll-like receptor signalling in atherosclerosis.Curr. Opin. Lipidol. 2006; 17: 527-533Crossref PubMed Scopus (94) Google Scholar). This could restrict TLR4 signaling in endothelial cells to only the MyD88 pathway. Curiously, CD14, the cofactor for both TLR2 and TLR4, was shown to be irrelevant to atherosclerosis in apo E−/− mice (37Bjo¨rkbacka H. Multiple roles of Toll-like receptor signalling in atherosclerosis.Curr. Opin. Lipidol. 2006; 17: 527-533Crossref PubMed Scopus (94) Google Scholar). TLR3, 7, and 9 may also participate in atherosclerosis (38Marshak-Rothstein A. Toll-like receptors in systemic sutoimmune disease.Nat. Rev. Immunol. 2006; 6: 823-835Crossref PubMed Scopus (890) Google Scholar, 39Finberg R.W. Wang J.P. Kurt-Jones E.A. Toll like receptors and viruses.Rev. Med. Virol. 2007; 17: 35-43Crossref PubMed Scopus (74) Google Scholar). For example, murine cytomegalovirus exacerbates atherosclerosis and is a ligand for TLR3 and TLR9 (39Finberg R.W. Wang J.P. Kurt-Jones E.A. Toll like receptors and viruses.Rev. Med. Virol. 2007; 17: 35-43Crossref PubMed Scopus (74) Google Scholar, 40Berencsi K. Endresz V. Klurfeld D. Kari L. Kritchevsky D. Gonczol E. Early atherosclerotic plaques in the aorta following cytomegalovirus infection.Cell Adhes. Commun. 1998; 5: 39-47Crossref PubMed Google Scholar). Coxsackie B virus is an agonist for TLR7 and promotes cardiac lipid accumulation in mice (41Ilba¨ck N.G. Mohammed A. Fohlman J. Friman G. Cardiovascular lipid accumulation with Coxsackie B virus infection in mice.Am. J. Pathol. 1990; 136: 159-167PubMed Google Scholar). Herpes simplex virus is a ligand for TLR9 (42Lund J. Sato A. Akira S. Medzhitov R. Iwasaki A. Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells.J. Exp. Med. 2003; 198: 513-520Crossref PubMed Scopus (1009) Google Scholar) and promotes murine atherosclerosis (43Morré S.A. Stooker W. Lagrand W.K. Brule A.J.C.Van den Niessen H.W.M. Microorganisms in the aetiology of atherosclerosis.J. Clin. Pathol. 2000; 53: 647-654Crossref PubMed Scopus (53) Google Scholar). Finally, antibody complexes of endogenous RNA and DNA are believed to be triggers for autoimmune disease and there is a strong link between autoimmune disease and atherosclerosis (44Sherer Y. Shoenfeld Y. Mechanisms of disease: atherosclerosis in autoimmune diseases.Nat. Clin. Pract. Rheumatol. 2006; 2: 99-106Crossref PubMed Scopus (304) Google Scholar). Together, this evidence, although indirect, supports the idea that activation of TLRs 3, 7, and 9 also promote atherosclerosis. TLR agonists can be either endogenous, such as products of sterile tissue damage (45Jiang D. Liang J. Fan J. Yu S. Chen S. Luo Y. Prestwich G.D. Mascarenhas M.M. Garg H.G. Quinn D.A. al et Regulation of lung injury and repair by Toll-like receptors and hyaluronan.Nat. Med. 2005; 11: 1173-1179Crossref PubMed Scopus (1152) Google Scholar), or exogenous, such as pathogens. The term “endogenous agonist” is used to refer to disease-associated TLR ligands that arise in mice that are not exposed by direct manipulation to known additional exogenous agonists, such as pathogenic organisms or synthetic mimics of components of pathogenic organisms. One might use the phrase “or unknown endemic exogenous agonist” because the hyperlipidemic mice are not truly sterile, gnotobiotic animals. Study mice are healthy and are kept in pathogen-free rooms, but of course also harbor a variety of commensal organisms. In fact, Erridge (46Erridge C. The roles of pathogen-associated molecular patterns in atherosclerosis.Trends Cardiovasc. Med. 2008; 18: 52-56Crossref PubMed Scopus (37) Google Scholar) has proposed that no true endogenous TLR agonists exist and that only infection- and commensal-derived agonists are recognized by TLRs. However, Wright et al. (47Wright S.D. Burton C. Hernandez M. Hassing H. Montenegro J. Mundt S. Patel S. Card D.J. Bergstrom A.Hermanowski-Vosatka, J.D. al et Infectious agents are not necessary for murine atherogenesis.J. Exp. Med. 2000; 191: 1437-1441Crossref PubMed Scopus (150) Google Scholar) have reported that true gnotobiotic hyperlipidemic mice do get atherosclerosis and this supports the more commonly held belief that endogenous TLR agonists exist. Importantly, our bone marrow transplantation experiments demonstrate that bone marrow-derived leukocytes do not participate in the early atheroprotective inflammatory responses observed in TLR2−/− mice exposed to only endogenous agonists, but do participate in the proatherogenic responses to an exogenous agonist, such as Pam3, a synthetic TLR2 agonist (25Mullick A.E. Tobias P.S. Curtiss L.K. Modulation of atherosclerosis in mice by Toll-like Receptor 2.J. Clin. Invest. 2005; 115: 3149-3156Crossref PubMed Scopus (465) Google Scholar). If TLR2 deficiency in hypercholesterolemic LDLr−/− mice decreases atheroma formation even in the absence of an administered exogenous agonist, what is the endogenous TLR2 agonist that promotes lesion formation via TLR2-mediated cell activation? Although a proatherogenic role for oxidized lipoproteins and lipids is well established (48Erridge C. Spickett C.M. Oxidised phospholipid regulation of Toll-like receptor signalling.Redox Rep. 2007; 12: 76-80Crossref PubMed Scopus (18) Google Scholar), their role as TLR agonists has received minimal attention. Berliner et al. (49Walton K.A. Cole A.L. Yeh M. Subbanagounder G. Krutzik S.R. Modlin R.L. Lucas R.M. Nakai J. Smart E.J. Vora D.K. al et Specific phospholipid oxidation products inhibit ligand activation of Toll-like receptors 4 and 2.Arterioscler. Thromb. Vasc. Biol. 2003; 23: 1197-1203Crossref PubMed Scopus (169) Google Scholar) reported that one oxidized LDL phospholipid, specifically 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphorylcholine, is not a TLR2 agonist and Miller et al. (50Miller Y.I. Viriyakosol S. Binder C.J. Feramisco J.R. Kirkland T.N. Witztum J.L. Minimally modified LDL binds to CD14, induces macrophage spreading via TLR4/MD-2, and inhibits phagocytosis of apoptotic cells.J. Biol. 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These are high-mobility group box 1 protein (HMGB1), hyaluronic acid fragments, and biglycan. HMGB1 was previously known only as a nuclear transcription factor, but is now known also to be a secreted cytokine mediating inflammatory responses to injury and infection (52Lotze M.T. Tracey K.J. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal.Nat. Rev. Immunol. 2005; 5: 331-342Crossref PubMed Scopus (2001) Google Scholar). Abrogation of its activity in sepsis models improves survival. HMGB1 binds directly to TLR2 and TLR4 and is an activating ligand for both TLR2 and TLR4 (53Park J.S. He F.Gamboni-Robertson, Q. Svetkauskaite D. Kim J.Y. Strassheim D. Sohn J.W. Yamada S. Maruyama I. Banerjee A. al et High mobility group box 1 protein interacts with multiple Toll-like receptors.Am. J. Physiol. Cell Physiol. 2006; 290: C917-C924Crossref PubMed Scopus (785) Google Scholar). HMGB1 has two DNA binding domains, the so-called A-box and B-box, as well as a long acidic tail. The B-box is responsible for inflammatory responses and antibodies to the B-box are therapeutically useful. By contrast, the A-box is antiinflammatory and is therapeutically useful in models of endotoxemia, sepsis, and arthritis (54Kokkola R. Li J. Sundberg E. Aveberger A.C. Palmblad K. Yang H. Tracey K.J. Andersson U. Harris H.E. 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: 2052-2058Crossref PubMed Scopus (273) Google Scholar, 55Yang H. Ochani M. Li J. Qiang X. Tanovic M. Harris H.E. Susarla S.M. Ulloa L. Wang H. DiRaimo R. al et Reversing established sepsis with antagonists of endogenous high-mobility group box 1.Proc. Natl. Acad. Sci. USA. 2004; 101: 296-301Crossref PubMed Scopus (976) Google Scholar). 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• W2003013587 created "2016-06-24" @default.
• W2003013587 creator A5013807783 @default.
• W2003013587 creator A5037380925 @default.
• W2003013587 date "2009-04-01" @default.
• W2003013587 modified "2023-10-11" @default.
• W2003013587 title "Emerging role of Toll-like receptors in atherosclerosis" @default.
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