Published online before print November 29, 2007, doi: 10.1161/CIRCRESAHA.107.157990
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Submitted on June 17, 2007
Revised on November 4, 2007
Accepted on November 19, 2007
Extracellular Matrix Metalloproteinase Inducer (CD147) Is a Novel Receptor on Platelets, Activates Platelets, and Augments Nuclear Factor 
B–Dependent Inflammation in Monocytes
Roland Schmidt *;
From the Deutsches Herzzentrum and I. Medizinische Klinik (R.S., S.F., A.S.) and III. Medizinische Klinik (P.J.), Klinikum rechts der Isar, Technische Universität München, Germany; Corimmun GmbH (A.B., A.G., M.U.), Martinsried, Germany; Mikrobiologie, Virologie, und Infektionsepidemiologie Hygiene und Umweltmedizin für Laboratoriumsmedizin Dr. Löer, Dr. Treder, und Kollegen (P.C.), Muenster, Germany; Forschungszentrum für Umwelt und Gesundheit (A.W.), Oberschleissheim, Germany; Department of Internal Medicine (N.D.T.), Eccles Institute of Human Genetics, University of Utah, Salt Lake City; and Medizinische Klinik III (S.L., M.G., A.E.M.), Eberhard-Karls Universität Tübingen, Germany.
* To whom correspondence should be addressed. E-mail: rolschmidt{at}yahoo.de.
In atherosclerosis, circulating platelets interact with endothelial cells and monocytes, leading to cell activation and enhanced recruitment of leukocytes into the vascular wall. The invasion of monocytes is accompanied by overexpression of matrix metalloproteinases (MMPs), which are thought to promote atherosclerosis and trigger plaque rupture. Following interaction with itself, the extracellular matrix metalloproteinase inducer (EMMPRIN) induces MMP synthesis via a little-known intracellular pathway. Recently, we showed upregulation of EMMPRIN on monocytes during acute myocardial infarction. EMMPRIN also stimulates secretion of MMP-9 by monocytes and of MMP-2 by smooth muscle cells, indicating that it may be an important regulator of MMP activity. Expression of EMMPRIN on platelets has not been described until now. Here, we demonstrate that resting platelets show low surface expression of EMMPRIN, which is upregulated by various platelet stimulators (flow cytometry). EMMPRIN is located in the open canalicular system and in 
granules of platelets (according to electron microscopy and sucrose gradient ultracentrifugation). Platelet stimulation with recombinant EMMPRIN-Fc induced surface expression of CD40L and P-selectin (according to flow cytometry), suggesting that EMMPRIN-EMMPRIN interaction activates platelets. Coincubation of platelets with monocytes induced EMMPRIN-mediated nuclear factor 
B activation (according to Western blot) in monocytes with increased MMP-9 (zymography), interleukin-6, and tumor necrosis factor- secretion (according to ELISA) by monocytes. In conclusion, EMMPRIN displays a new platelet receptor that is upregulated on activated platelets. Binding of EMMPRIN to platelets fosters platelet degranulation. Platelet–monocyte interactions via EMMPRIN stimulate nuclear factor B–driven inflammatory pathways in monocytes, such as MMP and cytokine induction. Thus, EMMPRIN may represent a novel target to diminish the burden of protease activity and inflammation in atherosclerosis.
Key words: platelet receptor • inflammation • leukocytes • metalloproteinases • plaque
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