EMMPRIN (CD147/basigin) mediates platelet–monocyte interactions in vivo and augments monocyte recruitment to the vascular wall

Abstract

Summary. Background: Platelets play a central role in hemostasis, in inflammatory diseases such as atherosclerosis, and during thrombus formation following vascular injury. Thereby, platelets interact intensively with monocytes and enhance their recruitment to the vascular wall. Objectives: To investigate the role of the extracellular matrix metalloproteinase inducer (EMMPRIN) in platelet-monocyte interactions. Methods and Results: Isolated human monocytes were perfused in vitro over firmly adherent platelets to allow investigation of the role of EMMPRIN in platelet-monocyte interactions under flow conditions. Monocytes readily bound to surface-adherent platelets. Both antibody blockade and gene silencing of monocyte EMMPRIN substantially attenuated firm adhesion of monocytes to platelets at arterial and venous shear rates. In vivo, platelet interactions with the murine monocyte cell line ANA-1 were significantly decreased when ANA-1 cells were pretreated with EMMPRIN-silencing small interfering RNA prior to injection into wild-type mice. Using intravital microscopy, we showed that recruitment of EMMPRIN-silenced ANA-1 to the injured carotid artery was significantly reduced as compared with control cells. Further silencing of EMMPRIN resulted in significantly fewer ANA-1-platelet aggregates in the mouse circulation as determined by flow cytometry. Finally, we identified glycoprotein (GP)VI as a critical corresponding receptor on platelets that mediates interaction with monocyte EMMPRIN. Thus, blocking of GPVI inhibited the effect of EMMPRIN on firm monocyte adhesion to platelets under arterial flow conditions in vitro, and abrogated EMMPRINmediated platelet-monocyte aggregate formation in vivo. Conclusions: EMMPRIN supports platelet-monocyte interactions and promotes monocyte recruitment to the arterial wall. Therefore, EMMPRIN might represent a novel target to reduce vascular inflammation and atherosclerotic lesion development.

Single platelets seal neutrophil-induced vascular breaches via GPVI during immune-complex–mediated inflammation in mice

“…33,34 In this context, it is interesting to note that the extracellular matrix metalloproteinase inducer (EMMPRIN) was recently identified as a leukocyte counterreceptor for GPVI expressed by neutrophils. 35,36 When addressing the extent of endothelial damage during the early phase of the rpA reaction, we observed that the endothelial lining was generally preserved but displayed alterations in regions of neutrophil infiltration, thus suggesting that endothelial injury and/or endothelial retraction contribute to inflammatory bleeding. Surprisingly, whether in GPVI 2/2 or thrombocytopenic mice, not all vessels supporting neutrophil infiltration bled.…”

Platelets Mediate Oxidized Low-Density Lipoprotein–Induced Monocyte Extravasation and Foam Cell Formation

“…The observed effects of OxLDL on platelet-monocyte interactions were dependent on the concentration and the degree of oxidative modification of LDL. Although platelet-monocyte interactions involve a variety of receptor-counter-receptor pairs, such as CD147/basigin or CD11b/CD18-glycoprotein Ib α (GPIbα), 29,30 and are also modulated by secreted soluble mediators, such as CXC motif ligand 16 (CXCL16) or CX3-C motif ligand 1 (CX3CL1), 31,32 our findings reinforce P-selectin as the key initial mediator for platelet-leukocyte interactions because blocking P-selectin-PSGL-1 interactions virtually abrogated platelet interaction with monocytes. P-selectin has previously been shown to be involved in the development and exacerbation of atherosclerotic lesions by bridging platelets to leukocytes.…”

The role of leukocytes in thrombosis

“…70 Signaling through PSGL-1 rapidly upregulates leukocyte expression of aMb2 71 that binds platelet GPIba 72 or GPIIbIIIa via a fibrinogen intermediate ( Figure 3B). 73 The complexes are further stabilized by multiple receptor-ligand interactions including CD40-CD40 ligand, 74 extracellular matrix metalloproteinase inducer-glycoprotein VI (GPVI), 75 lymphocyte function-associated antigen 1-ICAM-2, 76 and junctional adhesion molecule-C-aMb2. 77 PSGL-1 engagement can also activate cooperative signaling through NF-kB to induce the production of proinflammatory cytokines.…”