Abstract
Atherosclerosis is a chronic inflammatory disease in which both innate and adaptive immunity are involved. Although there have been major advances in the involvement of toll-like receptor 4 (TLR4) and CD36 in the initiation and development of this disease, detailed mechanisms remain unknown. Here, we show that tenascin-C (TN-C) can stimulate foam cell formation and this can be inhibited by a TLR4-blocking antibody or CD36 gene silencing. Our results identify TN-C-TLR4 activation as a common molecular mechanism in oxLDL-stimulated foam cell formation and atherosclerosis. In addition, CD36 is the major scavenger receptor responsible for the TN-C-mediated foam cell formation. Taken together, we have identified that TNC produced by oxLDL-stimulated macrophages increases foam cell formation through TLR4 and scavenger receptor CD36.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Amin, K., Lúdviksdóttir, D., Janson, C., Nettelbladt, O., Gudbjórnsson, B., Valtysdottir, S., Björnsson, E., Roomans, G., Boman, G., and Seveus, L. (2001). Inflammation and structural changes in the airways of patients with primary Sjögren’s syndrome. Respir. Med. 95, 904–910.
Andersson, J., Libby, P., and Hansson, G.K. (2010). Adaptive immunity and atherosclerosis. Clin. Immun. 134, 33–46.
Ashraf, M.Z., and Gupta, N. (2011). Scavenger receptors: implications in atherothrombotic disorders. Int. J. Biochem. Cell Biol. 43, 697–700.
Chang, Y.C., Huang, K.X., Huang, A.C., Ho, Y.C., and Wang, C.J. (2006). Hibiscus anthocyanins-rich extract inhibited LDL oxidation and oxLDL-mediated macrophages apoptosis. Food Chem. Toxicol. 44, 1015–1023.
Chiquet-Ehrismann, R., and Chiquet, M. (2003). Tenascins: regulation and putative functions during pathological stress. J. Pathol. 200, 488–499.
Feng, X., Zhang, Y., Xu, R., Xie, X., Tao, L., Gao, H., Gao, Y., He, Z., and Wang, H. (2010). Lipopolysaccharide up-regulates the expression of Fc [alpha]/[mu] receptor and promotes the binding of oxidized low-density lipoprotein and its IgM antibody complex to activated human macrophages. Atherosclerosis 208, 396–405.
Hajjar, D.P., and Haberland, M.E. (1997). Lipoprotein trafficking in vascular cells. J. Biol. Chem. 272, 22975.
Han, J., Hajjar, D.P., Febbraio, M., and Nicholson, A.C. (1997). Native and modified low density lipoproteins increase the functional expression of the macrophage class B scavenger receptor, CD36. J. Biol. Chem. 272, 21654.
Hansson, G.K. (2005). Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med. 352, 1685–1695.
Hoebe, K., Georgel, P., Rutschmann, S., Du, X., Mudd, S., Crozat, K., Sovath, S., Shamel, L., Hartung, T., and Zähringer, U. (2005). CD36 is a sensor of diacylglycerides. Nature 433, 523–527.
Howell, K.W., Meng, X., Fullerton, D.A., Jin, C., Reece, T.B., and Cleveland Jr., J.C. (2011). Toll-like receptor 4 mediates oxidized LDL-induced macrophage differentiation to foam cells. J. Surg. Res. 171, 27–31.
Ishigaki, Y., Katagiri, H., Gao, J., Yamada, T., Imai, J., Uno, K., Hasegawa, Y., Kaneko, K., Ogihara, T., and Ishihara, H. (2008). Impact of plasma oxidized low-density lipoprotein removal on atherosclerosis. Circulation 118, 75–83.
Ito, T., Yamada, S., and Shiomi, M. (2004). Progression of coronary atherosclerosis relates to the onset of myocardial infarction in an animal model of spontaneous myocardial infarction (WHHLMI rabbits). Exp. Animals 53, 339–346.
Jiang, L., Wei, X., Yi, D., Xu, P., Liu, H., Chang, Q., Yang, S., Li, Z., Gao, H., and Hao, G. (2009). Synergistic effects of cyclic strain and Th1-like cytokines on tenascin-C production by rheumatic aortic valve interstitial cells. Clin. Exp. Immunol. 155, 216–223.
Jovinge, S., Ares, M.P.S., Kallin, B., and Nilsson, J. (1996). Human monocytes/macrophages release TNF-α in response to ox-LDL. Arterioscler. Thromb. Vasc. Biol. 16, 1573–1579.
Khan, Z.A., Cukiernik, M., Gonder, J.R., and Chakrabarti, S. (2004). Oncofetal fibronectin in diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 45, 287.
Kim, M., Sandra, S., Anna, M.P., Julia, I., Annette, T., Emma, C., Stefan, D., Nidhi, S., Masahide, K., Gertraud, O., et al. (2009). Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nat. Med. 15, 774–781.
Lahoute, C., Herbin, O., Mallat, Z., and Tedgui, A. (2011). Adaptive immunity in atherosclerosis: mechanisms and future therapeutic targets. Nat. Rev. Cardiol. 8, 348–358.
Libby, P. (2006) The immune response in atherosclerosis: a double-edged sword. Nat. Rev. Immunol. 6, 508–519.
Loots, M.A.M., Lamme, E.N., Zeegelaar, J., Mekkes, J.R., Bos, J.D., and Middelkoop, E. (1998). Differences in cellular infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds. J. Invest. Dermatol. 111, 850–857.
Midwood, K., Sacre, S., Piccinini, A.M., Inglis, J., Trebaul, A., Chan, E., Drexler, S., Sofat, N., Kashiwagi, M., and Orend, G. (2009). Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nat. Med. 15, 774–780.
Midwood, K.S., Hussenet, T., Langlois, B., and Orend, G. (2011). Advances in tenascin-C biology. Cell. Mol. Life Sci. 68, 3175–3199.
Munteanu, A., Taddei, M., Tamburini, I., Bergamini, E., Azzi, A., and Zingg, J.M. (2006). Antagonistic effects of oxidized low density lipoprotein and α-Tocopherol on CD36 scavenger receptor expression in monocytes. J. Biol. Chem. 281, 6489–6497.
Podrez, E.A., Byzova, T.V., Febbraio, M., Salomon, R.G., Ma, Y., Valiyaveettil, M., Poliakov, E., Sun, M., Finton, P.J., and Curtis, B.R. (2007). Platelet CD36 links hyperlipidemia, oxidant stress and a prothrombotic phenotype. Nat. Med. 13, 1086–1095.
Ricciarelli, R., Zingg, J.M., and Azzi, A. (2000). Vitamin E reduces the uptake of oxidized LDL by inhibiting CD36 scavenger receptor expression in cultured aortic smooth muscle cells. Circulation 102, 82–87.
Stewart, C.R., Stuart, L.M., Wilkinson, K., van Gils, J.M., Deng, J., Halle, A., Rayner, K.J., Boyer, L., Zhong, R., and Frazier, W.A. (2009). CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat. Immunol. 11, 155–161.
Stuart, L.M., Deng, J., Silver, J.M., Takahashi, K., Tseng, A.A., Hennessy, E.J., Ezekowitz, R.A.B., and Moore, K.J. (2005). Response to Staphylococcus aureus requires CD36-mediated phagocytosis triggered by the COOH-terminal cytoplasmic domain. J. Cell Biol. 170, 477–485.
Takeda, K., Kaisho, T., and Akira, S. (2003). Toll-like receptors. Ann. Rev. Immunol. 21, 335–376.
Tedgui, A., Owens III, A.P., and Mackman, N. (2011). Nobel prize in physiology or medicine. Arterioscler. Thromb. Vasc. Biol. 31, 2767–2768.
Udalova, I.A., Ruhmann, M., Thomson, S., and Midwood, K.S. (2011). Expression and immune function of tenascin-C. Crit. Rev. Immunol. 31, 115–145.
Watanabe, T., Hirata, M., Yoshikawa, Y., Nagafuchi, Y., and Toyoshima, H. (1985). Role of macrophages in atherosclerosis. Sequential observations of cholesterol-induced rabbit aortic lesion by the immunoperoxidase technique using monoclonal antimacrophage antibody. Lab. Invest. J. Tech. Methods Pathol. 53, 80.
Xu, X.H., Shah, P.K., Faure, E., Equils, O., Thomas, L., Fishbein, M.C., Luthringer, D., Xu, X.P., Rajavashisth, T.B., and Yano, J. (2001). Toll-like receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL. Circulation 104, 3103–3108.
Author information
Authors and Affiliations
Corresponding authors
Additional information
These authors contributed equally to this work.
About this article
Cite this article
Liu, R., He, Y., Li, B. et al. Tenascin-C produced by oxidized LDL-stimulated macrophages increases foam cell formation through toll-like receptor-4. Mol Cells 34, 35–41 (2012). https://doi.org/10.1007/s10059-012-0054-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10059-012-0054-x