Subscribe to RSS
DOI: 10.1160/TH05-07-0465
EMMPRIN (CD 147) is a central activator of extracellular matrix degradation by Chlamydia pneumoniae-infected monocytes.
Implications for plaque rupture Financial support: This work was supported by a grant to A. E. M. from the Wilhelm-Sander-Stiftung (2000. 113. 1).Publication History
Received
03 July 2005
Accepted after resubmission
11 November 2005
Publication Date:
28 November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/200601/lookinside/thumbnails/10-1160-th05-07-0465-1.jpg)
Summary
Chlamydia (C.) pneumoniae are thought to infect monocytes and use them as vectors into the vessel wall, where they may accelerate atherosclerosis. We investigated the effects of C. pneumoniae on monocytic matrix metalloproteinase (MMP) activation with focus on the role of the extracellular matrix metalloproteinase inducer EMMPRIN. Human monocytes or monocytic MonoMac6 cells were infected with C. pneumoniae. Infection enhanced mRNA-and surface expression of EMMPRIN and Membrane-type-1 Matrix Metalloproteinase (MT1-MMP), plus the secretion of MMP-7, MMP-9 and the urokinase receptor (uPAR). Chlamydial heat shock protein 60 was identified to be partially responsible for EMMPRIN and MMP-9 induction, while C. trachomatis-infection had no stimulatory effect, indicatinga C. pneumoniae-specific activation pathway. Suppression of EMMPRIN by gene silencing almost completely hindered the induction of MT1-MMP and MMP-9 by C. pneumoniae, suggesting a predominant regulatory role for EMMPRIN. Moreover, C. pneumoniae-infected monocytes exhibited increased MMP-and plasmin-dependent migration through “matrigel”. Additionally, incubation of SMCs with supernatants of C. pneumoniae-infected monocytes induced MMP-2 activation, which was inhibited by IL1-Receptor antagonist or anti-IL-6-mAb, indicating paracrine intercellular activation pathways. In conclusion,C. pneumoniae induce MMP activity directly in monocytes through an EMMPRINdependent pathway and indirectly in SMCs via monocytederived cytokines.
* Current address of FJN: Herzzentrum Bad Krozingen, Südring 15, D-79189 Bad Krozingen, Germany
-
References
- 1 Lusis AJ. Atherosclerosis. Nature 2000; 407: 233-41.
- 2 May AE, Neumann FJ, Preissner KT. The relevance of blood cell vessel wall interactions for vascular thrombotic disease. Thromb Haemost 1999; 82: 962-9.
- 3 Libby P. Current Concepts of the pathogenesis of acute coronary syndromes. Circulation 2002; 104: 365-72.
- 4 Neumann FJ. Chlamydia pneumoniae-atherosclerosis link: a sound concept in search for clinical relevance. Circulation 2002; 106: 2428-33.
- 5 Danesh J, Collins R, Peto R. Chronic infections and coronary heart disease: Is there a link?. Lancet 1997; 350: 430-6.
- 6 Maass M, Bartels C, Kruger S. et al. Endovascular presence of Chlamydia pneumoniae DNA is a generalized phenomenon in atherosclerotic vascular disease. Atherosclerosis 1998; 140: 25-30.
- 7 Muhlestein JB, Hammond EH, Carlquist JF. et al. Increased incidence of Chlamydia species within the coronary artery of patients with symptomatic atherosclerotic versus other form of cardiovascular disease. J Am Coll Cardiol 1996; 27: 1555-61.
- 8 Moazed TC, Kuo CC, Grayston JT. et al. Evidence of systemic dissemination of Chlamydia pneumoniae via macrophages in the mouse. J Infect Dis 1998; 177: 1322-5.
- 9 Redecke V, Dalhoff K, Bohnet S. et al. Interaction of Chlamydia pneumoniae and human alveolar macrophages: infection and inflammatory response. Am J Respir. Cell Mol Biol 1998; 19: 721-7.
- 10 May AE, Redecke V, Grüner S. et al. Recruitment of Chlamydia pneumoniae-infected macrophages to the carotid artery wall in noninfected, nonatherosclerotic mice. Arterioscler Thromb Vasc Biol 2003; 23: 789-94.
- 11 Vehmaan-Kreula P, Puolakkainen M, Sarvas M. et al. Chlamydia pneumoniae proteins induce secretion of the 92-kDa gelatinase by human monocytederived macrophages. Arterioscler Thromb Vasc Biol 2001; 21: 1-8.
- 12 Choi EY, Kim D, Hong BK. et al. Upregulation of extracellular matrix metalloproteinase inducer (EMMPRIN) and gelatinases in human atherosclerosis infected with Chlamydia pneumoniae: The potential role of Chlamydia pneumoniae infection in the progression of atherosclerosis. Exp Mol Med 2002; 34: 391-400.
- 13 Ezzahiri R, Stassen FR, Kurvers HA. et al. Chlamydia pneumoniae infection induces an unstable atherosclerotic plaque phenotype in LDL-receptor, ApoE double knockout mice. Eur J Vasc Endovasc Surg 2003; 26: 88-95.
- 14 Galis ZS, Khatri J. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res 2002; 90: 251-62.
- 15 May AE, Kanse SM, Chavakis T. et al. Molecular interactions between the urokinase receptor and integrins in the vasculature. Fibrinol Proteol 1998; 12: 205-12.
- 16 Belkin AM, Akimov SS, Zaritskaya LS. et al. Matrix-dependent proteolysis of surface transglutaminase by membrane-type metalloproteinase regulates cancer cell adhesion and locomotion. J Biol Chem 2001; 276: 8415-22.
- 17 Caudroy S, Polette M, Nawrocki-Raby B. et al. EMMPRIN-mediated MMP regulation in tumor and endothelial cells. Clin Exp Metastasis 2002; 19: 697-702.
- 18 Major TC, Liang L, Xiaokong L. et al. Extracellular matrix metalloproteinase inducer (EMMPRIN) is induced upon monocyte differentiation and is expressed in human atheroma. Arterioscler Thromb Vasc Biol 2002; 22: 1200-7.
- 19 Da Costa CU, Wantia N, Kirschning CJ. et al. Heat shock protein 60 from Chlamydia pneumoniae elicits an unusual set of inflammatory responses via Toll-like receptor 2 and 4 in vivo . Eur J Immunol 2004; 34: 2874-84.
- 20 Ziegler-Heitbrock HW, Thiel E, Futterer A. et al. Establishment of a human cell line (MonoMac 6) with characteristics of mature monocytes. Int. J Cancer 1988; 41: 456-61.
- 21 May AE, Kalsch T, Massberg S. et al. Engagement of glycoprotein IIb/IIIa (alpha(IIb)beta3) on platelets upregulates CD40L and triggers CD40L-dependent matrix degradation by endothelial cells. Circulation 2002; 106: 2111-7.
- 22 May AE, Kanse SM, Lund LR. et al. Urokinase receptor (CD87) regulates leukocyte recruitment via beta 2 integrins in vivo . J Exp Med 1998; 188: 1029-37.
- 23 May AE, Schmidt R, Kanse SM. et al. Urokinase receptor surface expression regulates monocyte adhesion in acute myocardial infarction. Blood 2002; 100: 3611-7.
- 24 Barille S, Bataille R, Rapp MJ. et al. Production of metalloproteinase-7 (matrilysin) by human myeloma cells and its potential involvement in metalloproteinase-2 activation. J Immunol 1999; 163: 5723-8.
- 25 Seiki M, Yana I. Roles of pericellular proteolysis by membrane type-1 matrix metalloproteinase in cancer invasion and angiogenesis. Cancer Sci 2003; 94: 569-74.
- 26 Preissner KT, Kanse SM, May AE. Urokinase receptor: a molecular organizer in cellular communication. Curr Opin Cell Biol 2000; 12: 621-8.
- 27 Kol A, Sukhova GK, Lichtman AH. et al. Chlamydial heat shock protein 60 localizes in human atheroma and regulates macrophage tumor necrosis factor-alpha and matrix metalloproteinase expression. Circulation 1998; 98: 300-7.
- 28 Netea MG, Selzman CH, Kullberg BJ. et al. Acellular components of Chlamydia pneumoniae stimulate cytokine production in human blood mononuclear cells. Eur. J. Immunol 2000; 30: 541-9.
- 29 Haug C, Lenz C, Diaz F. et al. Oxidized low-density lipoproteins stimulate extracellular matrix metalloproteinase Inducer (EMMPRIN) release by coronary smooth muscle cells. Arterioscler Thromb Vasc Biol 2004; 24: 1823-9.
- 30 Dechend R, Maass M, Gieffer J. et al. Chlamydia pnumoniae infection of vascular smooth muscle and endothelial cells activates NF-kappaB and induces tissue factor and PAI-1 expression: A potential link to accelerated arteriosclerosis. Circulation 1999; 100: 1369-73.
- 31 Dechend R, Gieffers J, Dietz R, Joerres A, Rupp J, Luft FC, Maass M. Hydroxymethylglutaryl coenzyme A reductase inhibition reduces Chlamydia pneumoniae-induced cell interaction and activation. Circulation 2003; 108: 261-5.
- 32 Saikku P, Leinonen M, Mattila K. et al. Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet 1988; 29: 983-6.
- 33 Hu H, Pierce GN, Zhong G. The atherogenic effects of chlamydia are dependent on serum cholesterol and specific to Chlamydia pneumoniae . J Clin Invest 1999; 103: 747-53.
- 34 Bulut Y, Faure E, Thomas L. et al. Chlamydial heat shock protein 60 activates macrophages and endothelial cells through Toll-like receptor 4 and MD2 in a MyD88-dependent pathway. J Immunol 2002; 168: 1435-40.
- 35 Costa CP, Kirschning CJ, Busch D. et al. Role of chlamydial heat shock protein 60 in the stimulation of innate immune cells by Chlamydia pneumoniae. Eur J Immunol 2002; 32: 2460-70.
- 36 Kalayoglu MV, Indrawati RPMorrison. et al. Chlamydial virulence determinants in atherogenesis: the role of chlamydial lipopolysaccharide and heat shock protein 60 in macrophage-lipoprotein interactions. J Infect Dis 2000; 181: 483-9.
- 37 Krull M, Maass M, Suttorp N. et al. Chlamydophila pneumoniae. Mechanisms of target cell infection and activation. Thromb Haemost 2005; 94: 319-26.
- 38 Cannon CP, Braunwald E, McCabe CH. et al. , Pravastatin or atorvastatin evaluation and infection therapythrombolysis in myocardial infarction 22 investigators. Antibiotic treatment of Chlamydia pneumoniae after acute coronary syndrome. N Engl J Med 2005; 352: 1646-54.
- 39 Grayston JT, Kronmal RA, Jackson LA. et al. , ACES Investigators. Azithromycin for the secondary prevention of coronary events. N Engl J Med 2005; 352: 1637-45.
- 40 Gieffers J, Füllgraf H, Jahn J. et al. Chlamydia pneumoniae infection in circulating human monocytes is refractory to antibiotic treatment. Circulation 2001; 103: 351-6.