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Cathepsin S generates soluble CX3CL1 (fractalkine) in vascular smooth muscle cells

  • Urša Pečar Fonović , Zala Jevnikar and Janko Kos EMAIL logo
Published/Copyright: July 18, 2013

Abstract

CX3CL1 chemokine (fractalkine) is highly expressed by vascular smooth muscle cells (VSMCs) in atherosclerotic lesions. Its membrane-bound form promotes cell-cell interactions, whereas the soluble form induces chemotaxis of CX3CR1- expressing leukocytes. We show that the cysteine protease cathepsin S, expressed by VSMCs, is able to cleave membrane-anchored CX3CL1, releasing a 55-kDa fragment to the medium, thus regulating the adhesion of VSMCs and the capture of monocytes to the sites of atherogenesis. Moreover, strong co-localization of cathepsin S and CX3CL1 with a recycling endosome marker Rab11a suggests a processing of CX3CL1 in recycling endosomes during its redistribution to the plasma membrane.


Corresponding author: Janko Kos, Faculty of Pharmacy, University of Ljubljana, Askerceva 7, SI-1000 Ljubljana, Slovenia; and Department of Biotechnology, Jamova 39, Jozef Stefan Institute, SI-1000 Ljubljana, Slovenia

We would like to thank Dr. James McKerrow (UCSF) for the kind gift of LHVS inhibitor, DDr. Boris Turk (Jozef Stefan Institute) for the kind gift of recombinant human cathepsin S, and Prof. Roger Pain for the critical reading of the manuscript. This work was supported by Slovenia Research Agency grant P4-0127 (J.K.)

References

Bazan, J.F., Bacon, K.B., Hardiman, G., Wang, W., Soo, K., Rossi, D., Greaves, D.R., Zlotnik, A., and Schall, T.J. (1997). A new class of membrane-bound chemokine with a CX3C motif. Nature 385, 640–644.10.1038/385640a0Search in Google Scholar PubMed

Cheng, X.W., Kuzuya, M., Nakamura, K., Di, Q., Liu, Z., Sasaki, T., Kanda, S., Jin, H., Shi, G.P., Murohara, T., et al. (2006). Localization of cysteine protease, cathepsin S, to the surface of vascular smooth muscle cells by association with integrin αvβ3. Am. J. Pathol. 168, 685–694.10.2353/ajpath.2006.050295Search in Google Scholar PubMed PubMed Central

Clark, A.K., Yip, P.K., Grist, J., Gentry, C., Staniland, A.A., Marchand, F., Dehvari, M., Wotherspoon, G., Winter, J., Ullah, J., et al. (2007). Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc. Natl. Acad. Sci. USA 104, 10655–10660.10.1073/pnas.0610811104Search in Google Scholar PubMed PubMed Central

Garton, K.J., Gough, P.J., Blobel, C.P., Murphy, G., Graves, D.R., Dempsey, P.J., and Raines, E.W. (2001). Tumor necrosis factor-α-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1). J. Biol. Chem. 276, 37993–38001.10.1074/jbc.M106434200Search in Google Scholar PubMed

Hundhausen, C., Misztela, D., Berkhout, T.A., Broadway, N., Saftig, P., Reiss, K., Hartmann, D., Fahrenholz, F., Postina, R., Matthews, V., et al. (2003). The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion. Blood 102, 1186–1195.10.1182/blood-2002-12-3775Search in Google Scholar PubMed

Kos, J., Sekirnik, A., Kopitar, G., Cimerman, N., Kayser, K., Stremmer, A., Fiehn, W., and Werle, B. (2001). Cathepsin S in tumours, regional lymph nodes and sera of patients with lung cancer: relation to prognosis. Br. J. Cancer 85, 1193–1200.10.1054/bjoc.2001.2057Search in Google Scholar PubMed PubMed Central

Lesnik, P., Haskell, C.A., and Charo, I.F. (2003). Decreased atherosclerosis in CX3CR1-/- mice reveals a role for fractalkine in atherogenesis. J. Clin. Invest. 111, 333–340.10.1172/JCI15555Search in Google Scholar PubMed PubMed Central

Liu, G.Y., Kulasingam, V., Alexander, R.T., Touret, N., Fong, A.M., Patel, D.D., and Robinson, L.A. (2005). Recycling of the membrane-anchored chemokine, CX3CL1. J. Biol. Chem. 280, 19858–19866.10.1074/jbc.M413073200Search in Google Scholar PubMed

Ludwig, A., Berkhout, T., Moores, K., Groot, P., and Chapman, G. (2002). Fractalkine is expressed by smooth muscle cells in response to IFN-γ and TNF-α and is modulated by metalloproteinase activity. J. Immunol. 168, 604–612.10.4049/jimmunol.168.2.604Search in Google Scholar PubMed

Lutgens, E., Faber, B., Schapira, K., Evelo, C.T.A., van Haaften, R., Heeneman, S., Cleutjens, K.B.J.M., Bijnens, A.P., Beckers, L., Porter, J.G., et al. (2005). Gene Profiling in atherosclerosis reveals a key role for small inducible cytokines: validation using a novel monocyte chemoattractant protein monoclonal antibody. Circulation 111, 3443–3452.10.1161/CIRCULATIONAHA.104.510073Search in Google Scholar PubMed

Lützner, N. and Kalbacher, H. (2008). Quantifying cathepsin S activity in antigen presenting cells using a novel specific substrate. J. Biol. Chem. 283, 36185–36194.10.1074/jbc.M806500200Search in Google Scholar PubMed PubMed Central

Reape, T.J., Rayner, K., Manning, C.D., Gee, A.N., Barnette, M.S., Burnand, K.G., and Groot, P.H. (1999). Expression and cellular localization of the CC chemokines PARX and LC in human atherosclerotic plaques. Am. J. Pathol. 154, 365–374.10.1016/S0002-9440(10)65283-2Search in Google Scholar PubMed PubMed Central

Ruan, Y., Takahashi, K., and Naito, M. (1995). Immunohistochemical detection of macrophage-derived foam cells and macrophage colony-stimulating factor in pulmonary atherogenesis of cholesterol-fed rabbits. Pathol. Int. 45, 185–195.10.1111/j.1440-1827.1995.tb03441.xSearch in Google Scholar PubMed

Sukhova, G.K., Shi, G.P., Simon, D.I., Chapman, H.A., and Libby, P. (1998). Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. J. Clin. Invest. 102, 576–583.10.1172/JCI181Search in Google Scholar PubMed PubMed Central

Wang, J.M., Sica, A., Peri, G., Walter, S., Padura, I.M., Libby, P., Ceska, M., Lindley, I., Colotta, F., and Mantovani, A. (1991). Expression of monocyte chemotatic protein and interleukin-8 by cytokine-activated human vascular smooth muscle cells. Arterioscler. Thromb. 11, 1166–1174.10.1161/01.ATV.11.5.1166Search in Google Scholar PubMed

Received: 2013-5-21
Accepted: 2013-7-15
Published Online: 2013-07-18
Published in Print: 2013-10-01

©2013 by Walter de Gruyter Berlin Boston

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