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Stimulation of P2 (P2X₇) receptors in human dendritic cells induces the release of tissue factor-bearing microparticles

Marcello Baroni^*,1, Cinzia Pizzirani^,1, Mirko Pinotti^*, Davide Ferrari, Elena Adinolfi, Sara Calzavarini^*, Pierpaolo Caruso^*, Francesco Bernardi^* and Francesco Di Virgilio^,2

^* Departments of Biochemistry, and

Experimental and Diagnostic Medicine, and Interdisciplinary Center for the Study of Inflammation, University of Ferrara, Ferrara, Italy

²Correspondence: Department of Experimental and Diagnostic Medicine, Section of General Pathology, Via Borsari 46, 44100 Ferrara, Italy. E-mail: fdv{at}unife.it

Receptors for extracellular nucleotides are the focus of increasing attention for their ability to cause release of plasma membrane vesicles (microparticles, MPs). Here, we show that monocyte-derived human dendritic cells (DCs) stimulated with a P2X₇ receptor (P2X₇R) agonist undergo a large release of MPs endowed with procoagulant activity. Functional and Western blot studies revealed that MPs contain the membrane-bound form of tissue factor (TF), a glycoprotein acting as essential cofactor of activated factor VII and triggering blood coagulation. Quiescent DCs express the membrane-bound (full length), as well as truncated alternatively spliced TF forms. DC reactivity to anti-TF Abs disappeared almost completely on stimulation with ATP or benzoyl ATP (BzATP), as shown by immunoblot and confocal microscopy analysis. Concurrently, TF reactivity and activity appeared in the vesicular fraction, indicating that MPs are important carriers for the dissemination of full-length TF form. Activity of MP-bound TF, comparable to that of relipidated recombinant TF, was dose dependently inhibited by the addition of a specific anti-human TF antibody. We infer that a large fraction of this protein, and its procoagulant potential, are "deliverable" after physiological or pathological stimuli. These findings might have implications for triggering and propagating coagulation in healthy and atherosclerotic vessels.—Marcello Baroni, Cinzia Pizzirani, Mirko Pinotti, Davide Ferrari, Elena Adinolfi, Sara Calzavarini, Pierpaolo Caruso, Francesco Bernardi, and Francesco Di Virgilio. Stimulation of P2 (P2X₇) receptors in human dendritic cells induces the release of tissue factor-bearing microparticles.

Key Words: coagulation • inflammation • extracellular ATP • purinergic receptors

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