Abstract
Atherosclerosis was once thought to be solely a disease of lipid accumulation in the vessel wall. It does involve lipid accumulation, but inflammation appears to be an important driving factor. Consequently, our laboratory undertook to examine the role(s) of TLRs, and especially TLR2, in murine models of atherosclerosis.
Similar content being viewed by others
References
Lusis AJ (2000) Atherosclerosis. Nature 407:233–241
Ross R (1999) Atherosclerosis—an inflammatory disease. N Engl J Med 340:115–126
Jongstra-Bilen J, Haidari M, Zhu SN, Chen M, Guha D, Cybulsky MI (2006) Low-grade chronic inflammation in regions of the normal mouse arterial intima predisposed to atherosclerosis. J Exp Med 203:2073–2083
Blankenberg S, Yusuf S (2006) The inflammatory hypothesis: any progress in risk stratification and therapeutic targets? Circulation 114:1557–1560
Zieske AW, Malcom GT, Strong JP (2002) Natural history and risk factors of atherosclerosis in children and youth: the PDAY Study. Pediatr Pathol Mol Med 21:213–237
Soutar AK, Naoumova RP (2007) Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med 4:214–225
Van Doornum S, McColl G, Wicks IP (2002) Accelerated atherosclerosis: an extraarticular feature of rheumatoid arthritis? Arthritis Rheum 46:862–873
Triantafilou M, Gamper FGJ, Haston RM, Mouratis MA, Morath S, Hartung T, Triantafilou K (2006) Membrane sorting of Toll-like receptor (TLR)-2/6 and TLR2/1 heterodimers at the cell surface determines heterotypic associations with CD36 and intracellular targeting. J Biol Chem 281:31002–31011
Cao F, Castrillo A, Tontonoz P, Re F, Byrne GI (2007) Chlamydia pneumoniae-induced macrophage foam cell formation is mediated by Toll-like receptor 2. Infect Immun 75:753–759
Hauer AD, de Vos P, Peterse N, ten Cate H, van Berkel TJ, Stassen FR, Kuiper J (2006) Delivery of Chlamydia pneumoniae to the vessel wall aggravates atherosclerosis in LDLr−/− mice. Cardiovasc Res 69:280–288
Wasserman SM, Topper JN (2004) Adaptation of the endothelium to fluid flow: in vitro analyses of gene expression and in vivo implications. Vasc Med 9:35–45
Matharu NM, Rainger GE, Vohra R, Nash GB (2006) Effects of disturbed flow on endothelial cell function: pathogenic implications of modified leukocyte recruitment. Biorheology 43:31–44
Cunningham KS, Gotlieb AI (2005) The role of shear stress in the pathogenesis of atherosclerosis. Lab Invest 85:9–23
Dai G, Kaazempur-Mofrad MR, Natarajan S, Zhang Y, Vaughn S, Blackman BR, Kamm RD, Garcia-Cardena G, Gimbrone MA Jr (2004) Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and -resistant regions of human vasculature. Proc Natl Acad Sci U S A 101:14871–14876
Tzima E, Irani-Tehrani M, Kiosses WB, Dejana E, Schultz DA, Engelhardt B, Cao G, DeLisser H, Schwartz MA (2005) A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 437:426–431
Parmar KM, Larman HB, Dai G, Zhang Y, Wang ET, Moorthy SN, Kratz JR, Lin Z, Jain MK, Gimbrone MA Jr et al (2006) Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2. J Clin Invest 116:49–58
Dai G, Vaughn S, Zhang Y, Wang ET, Garcia-Cardena G, Gimbrone MA Jr (2007) Biomechanical forces in atherosclerosis-resistant vascular regions regulate endothelial redox balance via phosphoinositol 3-kinase/Akt-dependent activation of Nrf2. Circ Res 101:723–733
Ferwerda G, Girardin SE, Kullberg BJ, Le BL, de Jong DJ, Langenberg DM, van CR, Adema GJ, Ottenhoff TH, Van der Meer JW et al (2005) NOD2 and Toll-like receptors are nonredundant recognition systems of Mycobacterium tuberculosis. PLoS Pathog 1:279–285
Jiang D, Liang J, Fan J, Yu S, Chen S, Luo Y, Prestwich GD, Mascarenhas MM, Garg HG, Quinn DA et al (2005) Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med 11:1173–1179
Ishibashi S, Brown MS, Goldstein JL, Gerard RD, Hammer RE, Herz J (1993) Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J Clin Invest 92:883–893
Mullick AE, Tobias PS, Curtiss LK (2005) Modulation of atherosclerosis in mice by Toll-like receptor 2. J Clin Invest 115:3149–3156
Mullick AE, Tobias PS, Curtiss LK (2006) Toll-like receptors and atherosclerosis: key contributors in disease and health? Immunol Res 34:193–209
Boisvert WA, Spangenberg J, Curtiss LK (1995) Treatment of severe hypercholesterolemia in apolipoprotein E-deficient mice by bone marrow transplantation. J Clin Invest 96:1118–1124
Bjorkbacka H, Kunjathoor VV, Moore KJ, Koehn S, Ordija CM, Lee MA, Means T, Halmen K, Luster AD, Golenbock DT et al (2004) Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nat Med 10:416–421
Michelsen KS, Wong MH, Shah PK, Zhang W, Yano J, Doherty TM, Akira S, Rajavashisth TB, Arditi M (2004) 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 U S A 101:10679–10684
Dunzendorfer S, Lee HK, Tobias PS (2004) Flow-dependent regulation of endothelial Toll-like receptor 2 expression through inhibition of SP1 activity. Circ Res 95:684–691
Nijhuis MM, van der Graaf Y, Melief M-J, Schoneveld AH, de Kleijn DP, Laman JD, Pasterkamp G (2004) IgM antibody level against proinflammatory bacterial peptidoglycan is inversely correlated with extent of atherosclerotic disease. Atherosclerosis 173:245–251
Wright SD, Burton C, Hernandez M, Hassing H, Montenegro J, Mundt S, Patel S, Card DJ, Hermanowski-Vosatka A, Bergstrom JD et al (2000) Infectious agents are not necessary for murine atherogenesis. J Exp Med 191:1437–1442
Ostos MA, Recalde D, Zakin MM, Scott-Algara D (2002) Implication of natural killer T cells in atherosclerosis development during a LPS-induced chronic inflammation. FEBS Lett 519:23–29
Lehr HA, Sagban TA, Ihling C, Zahringer U, Hungerer KD, Blumrich M, Reifenberg K, Bhakdi S (2001) Immunopathogenesis of atherosclerosis: endotoxin accelerates atherosclerosis in rabbits on hypercholesterolemic diet. Circulation 104:914–920
Liu X, Ukai T, Yumoto H, Davey M, Goswami S, Gibson FC III, Genco CA (2007) Toll-like receptor 2 plays a critical role in the progression of atherosclerosis that is independent of dietary lipids. Atherosclerosis (in press)
Katsumi A, Orr AW, Tzima E, Schwartz MA (2004) Integrins in mechanotransduction. J Biol Chem 279:12001–12004
Mullick AE, Soldau K, Kiosses WB, Bell TA, Tobias PS, Curtiss LK (2007) Increased endothelial expression of Toll-like receptor 2 at sites of disturbed blood flow exacerbates early atherogenic events. J Exp Med, in press
Brunn GJ, Bungum MK, Johnson GB, Platt JL (2005) Conditional signaling by Toll-like receptor 4. FASEB J 19:872–874
Shinohara M, Hirata Ki, Yamashita T, Takaya T, Sasaki N, Shiraki R, Ueyama T, Emoto N, Inoue N, Yokoyama M et al (2007) Local overexpression of Toll-like receptors at the vessel wall induces atherosclerotic lesion formation. Synergism of TLR2 and TLR4. Arterioscler Thromb Vasc Biol 27:2384–2391
Park JS, Gamboni-Robertson F, He Q, Svetkauskaite D, Kim JY, Strassheim D, Sohn JW, Yamada S, Maruyama I, Banerjee A et al (2005) High mobility group BOx 1 protein (HMGB1) interacts with multiple toll like receptors. Am J Physiol Cell Physiol 290:C917–C924
Schaefer L, Babelova A, Kiss E, Hausser HJ, Baliova M, Krzyzankova M, Marsche G, Young MF, Mihalik D, Gotte M et al (2005) The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages. J Clin Invest 115:2223–2233
Termeer C, Benedix F, Sleeman J, Fieber C, Voith U, Ahrens T, Miyake K, Freudenberg M, Galanos C, Simon JC (2002) Oligosaccharides of hyaluronan activate dendritic cells via Toll-like receptor 4. J Exp Med 195:99–111
Li M, Carpio DF, Zheng Y, Bruzzo P, Singh V, Ouaaz F, Medzhitov RM, Beg AA (2001) An essential role of the NF-kappa B/Toll-like receptor pathway in induction of inflammatory and tissue-repair gene expression by necrotic cells. J Immunol 166:7128–7135
Cheng N, He R, Ye RD (2007) 7 A.D. Serum amyloid A is an endogenous ligand for Toll-like receptor 2. Arterioscler Thromb Vasc Biol, abstract book: 23–24 (abstract)
Jain MK, Ridker PM (2005) Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat Rev Drug Discov 4:977–987
Youn HS, Saitoh SI, Miyake K, Hwang DH (2006) Inhibition of homodimerization of Toll-like receptor 4 by curcumin. Biochem Pharmacol 72:62–69
Youn HS, Lee JY, Saitoh SI, Miyake K, Hwang DH (2006) Auranofin, as an anti-rheumatic gold compound, suppresses LPS-induced homodimerization of TLR4. Biochem Biophys Res Commun 350:866–871
Fort MM, Mozaffarian A, Stover AG, Correia JS, Johnson DA, Crane RT, Ulevitch RJ, Persing DH, Bielefeldt-Ohmann H, Probst P et al (2005) A synthetic TLR4 antagonist has anti-inflammatory effects in two murine models of inflammatory bowel disease. J Immunol 174:6416–6423
Shiozaki M, Iwano Y, Doi H, Tanaka D, Shimozato T, Kurakata S (2006) Syntheses of glucose derivatives of E5564-related compounds and their LPS-antagonistic activities. Carbohydr Res 341:811–822
Lee HK, Brown SJ, Rosen H, Tobias PS (2007) Application of beta-lactamase enzyme complementation to the high-throughput screening of Toll-like receptor signaling inhibitors. Mol Pharmacol 72:868–875
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Tobias, P.S., Curtiss, L.K. TLR2 in murine atherosclerosis. Semin Immunopathol 30, 23–27 (2008). https://doi.org/10.1007/s00281-007-0102-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00281-007-0102-3