Extracellular matrix metalloproteinase inducer (CD147) is a novel receptor on platelets, activates platelets, and augments nuclear factor kappaB-dependent inflammation in monocytes.
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 alpha 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 kappaB activation (according to Western blot) in monocytes with increased MMP-9 (zymography), interleukin-6, and tumor necrosis factor-alpha 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 kappaB-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.
Schmidt
Roland
R
Deutsches Herzzentrum und I. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Lazarettstr. 36, 80636 München, Germany. schmidtr@dhm.mhn.de
Bültmann
Andreas
A
Fischel
Sina
S
Gillitzer
Angelika
A
Cullen
Paul
P
Walch
Axel
A
Jost
Philipp
P
Ungerer
Martin
M
Tolley
Neal D
ND
Lindemann
Stephan
S
Gawaz
Meinrad
M
Schömig
Albert
A
May
Andreas E
AE
D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology; D051926:Basigin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism* / Q000648:ultrastructure; D023201:CD40 Ligand / Q000378:metabolism; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000378:metabolism / Q000648:ultrastructure; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism* / Q000648:ultrastructure; D016328:NF-kappa B / Q000378:metabolism*; D019007:P-Selectin / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D022142:Secretory Vesicles / Q000378:metabolism / Q000648:ultrastructure; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C497886:BSG protein, human; C508600:IL6 protein, human; D007127:Immunoglobulin Constant Regions; D015850:Interleukin-6; D016328:NF-kappa B; D019007:P-Selectin; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D051926:Basigin; D023201:CD40 Ligand; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9