Platelets are a previously unrecognised source of MIF

Abstract

Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine with chemokine-like functions and a role in atherogenesis. MIF is secreted by various cells including endothelial cells and macrophages. Platelets are another prominent cell type with a role in atherogenesis and are a rich source of atherogenic chemokines. We asked whether platelets express and secrete MIF. In comparison, CXCL12 release was determined. We examined the subcellular localisation of MIF in platelets/megakaryocytes, studied its co-localisation with other platelet-derived mediators and asked whether platelets contain MIF mRNA. Moreover, we probed the functional role of platelet-derived MIF in inflammatory cell recruitment. Using Western blot and ELISA, we demonstrated and quantitated MIF protein in human and mouse platelets. Applying confocal-microscopy, MIF was found to localise in granular-like structures, but did not co-localise with known platelet cytokines. qPCR indicated that platelets contain low levels of MIF mRNA. ELISA measurements from human platelet supernatants showed that, whereas thrombin and collagen triggered the release of MIF and CXCL12, ADP and oxidised LDL promoted CXCL12 but not MIF secretion. Using Transwell assays, we demonstrated that platelet supernatants promoted monocyte chemotaxis and that this was blocked by neutralising MIF antibodies.This is the first report demonstrating MIF secretion from activated platelets, suggesting that platelets are a previously unrecognised source of MIF in inflammatory processes. There are distinct activating stimuli for MIF and CXCL12 secretion. A substantial portion of the chemotactic capacity of stimulated platelet supernatants is contributed by MIF, suggesting a role for platelet-derived MIF in atherogenic cell recruitment.

Toll like receptor 2/1 mediated platelet adhesion and activation on bacterial mimetic surfaces is dependent on src/Syk-signaling and purinergic receptor P2X1 and P2Y12 activation

“…In mice, RANTES secretion leads to migration of monocytes and T-cells and to their deposition on endothelial cells in atherosclerotic lesions. 33 MIF plays a crucial role in the atherosclerotic inflammatory process and has been proposed to be a biomarker for disease severity; however, the full mechanism behind its actions is not yet elucidated. 17 This study shows that platelet adhesion to Pam 3 CSK 4 -coated surfaces leads to secretion of RANTES over time and that no considerable differences could be seen between immobilized and soluble Pam 3 CSK 4 .…”

Platelets in Inflammation: Regulation of Leukocyte Activities and Vascular Repair

“…The panel of chemokines found in platelets is extensive and includes platelet factor 4, stromal cell-derived factor-1, macrophage inflammatory protein-1α (MIP-1α), regulated upon activation, normal T cell expressed and secreted (RANTES), and thymus and activation-regulated chemokine (TARC), to name but a few ( 4 , 24 , 42 ). Like P-selectin, these chemokines are stored in platelet granules and their contribution to recruitment of leukocytes by platelets highlights the need for platelet activation in this process.…”

Platelets in Inflammation and Atherogenesis

“…In atherosclerosis, platelets are known to contribute to early steps of this chronic vascular pathology (Figure 2 ) such as endothelial dysfunction ( 101 , 102 ), but also to final events such as rupture of the vulnerable plaque [( 103 ), see also Figure 4 ]. For instance, platelets participate in atherogenesis by chemokine release ( 79 , 104 , 105 ), surface association of oxLDL ( 106 ), direct cell–cell interaction ( 107 , 108 ), release of microparticles ( 109 ), and provision of inflammatory mediators [( 110 ), see also Figure 3 ]. Platelets within the atherosclerotic plaque may remain activated for a long time providing for proinflammatory IL-1β production [( 111 ), see also Figure 3 ].…”