Platelets Recruit Human Dendritic Cells Via Mac-1/JAM-C Interaction and Modulate Dendritic Cell Function In Vitro

Abstract

Objective-Thrombotic events and immunoinflammatory processes take place next to each other during vascular remodeling in atherosclerotic lesions. In this study we investigated the interaction of platelets with dendritic cells (DCs). Methods and Results-The rolling of DCs on platelets was mediated by PSGL-1. Firm adhesion of DCs was mediated through integrin ␣ M ␤ 2 (Mac-1). In vivo, adhesion of DCs to injured carotid arteries in mice was mediated by platelets. Pretreatment with soluble GPVI, which inhibits platelet adhesion to collagen, substantially reduced recruitment of DCs to the injured vessel wall. In addition, preincubation of DCs with sJAM-C significantly reduced their adhesion to platelets. Coincubation of DCs with platelets induced maturation of DCs, as shown by enhanced expression of CD83. In the presence of platelets, DC-induced lymphocyte proliferation was significantly enhanced. Moreover, coincubation of DCs with platelets resulted in platelet phagocytosis by DCs, as verified by different cell phagocytosis assays. Finally, platelet/DC interaction resulted in apoptosis of DCs mediated by a JAM-Cdependent mechanism. Conclusions-Recruitment of DCs by platelets, which is mediated via CD11b/CD18 (Mac-1) and platelet JAM-C, leads to DC activation and platelet phagocytosis. This process may be of importance for progression of atherosclerotic lesions. 3 In atherosclerotic plaques, the number of DCs is substantially enhanced and DCs preferentially accumulate at rupture-prone regions. 4,5 Recently, DCs were shown to accumulate in the intima of atherosclerosis-predisposed regions of the aorta of C57BL/6 mice. 6 However, the mechanisms involved in the recruitment of circulating DCs at site of vascular lesions are poorly understood so far.It is well recognized that platelets rapidly adhere to the extracellular matrix of the subendothelium at sites of vascular lesions. If this process is controlled, platelets passivate vascular injury and initiate the healing process. 1 However, uncontrolled platelet-mediated thrombus formation leads to acute thrombotic occlusion or plaque progression resulting in, eg, acute coronary syndrome. 7 Platelet-mediated cell recruitment to the atherosclerotic plaque plays a central role for vascular repair mechanisms. DCs participate both in the innate and adaptive immune system and represent highly specialized antigen-presenting cells. 8 Thereby, they are capable of stimulating naive, memory, and effector T-cells, as well as activating natural killer cells. 8 Proteins are internalized by phagocytosis, degraded into short peptides, and presented via the MHC II receptors. 9 During maturation, DCs express various adhesion receptors, which enable DCs to interact with other cell types and mediate homing of DCs to target tissues. 4,8 Original The present study evaluates the role of platelets for DC adhesion to vascular lesions and shows that platelets play a critical role for the recruitment and function of DCs. Materials and MethodsDCs were generated from buffy coats derived fr...

Engagement of αIIbβ3 (GPIIb/IIIa) with ανβ3 Integrin Mediates Interaction of Melanoma Cells with Platelets

“…In contrast, we observed a robust increase in adhesivity of murine and human melanoma cells in the presence of platelets in various settings in vitro. Adherent platelets present potent adhesion receptors such as JAM-C, P-Selectin, GPIb␣, or GPIIb/IIIa to other circulating cells providing a platform for a potent cellular bridging mechanism to the vascular wall (20,25,(52)(53)(54)(55)(56). Recently, glycoprotein Ib␣ (GPIb␣), the second most abundant receptor expressed on platelets, has been reported to be significantly involved in melanoma metastasis, as the functional absence of GPIb␣ correlated with a clear reduction in the number of lung metastatic foci in vivo (57).…”

“…Human platelets were isolated as described previously (25)(26)(27). Briefly, venous blood was drawn from the antecubital vein of healthy volunteers and collected in acid/citrate/dextrose buffer.…”

“…Static Adhesion Assay-Static adhesion assays and dynamic adhesion assays were performed as described previously (25,35,36). For static adhesion, 96-well polystyrene plates (Falcon) were coated with murine or human platelets (1 ϫ 10 8 /ml) for 2 h, washed with Tyrode's buffer to remove nonadherent platelets, and blocked for 30 min with 1% BSA in Tyrode's buffer.…”

The integrin Mac-1 (CR3) mediates internalization and directsBacillus anthracisspores into professional phagocytes

“…34 and 35. Because both subunits of Mac-1 are highly expressed not only on macrophages but also on DCs (36)(37)(38), available data strongly suggest that spore internalization by DCs may also involve Mac-1.…”

European Perspectives

“…For 3 years he studied how the cells of the innate immune system influence inflammation and disease. 2,3 Professor Langer is particularly fascinated by dendritic cells, 4 and believes that an investigation into dendritic cells as modulators of inflammation in the early phase of disease is a promising research area and could open new directions in cardiovascular research and medicine.…”