title: FLow-induced PRotrusions (FLIPRs): a platelet-derived platform for the retrieval of microparticles by monocytes and neutrophils.
abstract: BACKGROUND
  Platelets are the most important cells in the primary prevention of blood loss after injury. In addition, platelets are at the interface between circulating leukocytes and the (sub)endothelium regulating inflammatory responses.
  
  
  OBJECTIVE
  Our aim was to study the dynamic process that leads to the formation of procoagulant and proinflammatory platelets under physiological flow.
  
  
  RESULTS
  In the present study, we describe the formation of extremely long, negatively charged membrane strands that emerge from platelets adhered under flow. These flow-induced protrusions (FLIPRs) are formed in vitro on different physiological substrates and are also detected in vivo in a mouse carotid injury model. FLIPRs are formed downstream the adherent and activated platelets and reach lengths of 250 μm. FLIPR formation is shear-dependent and requires cyclophilin D, calpain, and Rac1 activation. It is accompanied by a disassembly of the F-actin and microtubule organization. Monocytes and neutrophils roll over FLIPRs in a P-selectin/P-selectin glycoprotein ligand-1-dependent manner, retrieving fragments of FLIPRs as microparticles on their surface. Consequently, monocytes and neutrophils become activated, as demonstrated by increased CD11b expression and L-selectin shedding.
  
  
  CONCLUSIONS
  The formation of long platelet membrane extensions, such as the ones presented in our flow model, may pave the way to generate an increased membrane surface for interaction with monocytes and neutrophils. Our study provides a mechanistic model for platelet membrane transfer and the generation of monocyte/neutrophil-microparticle complexes. We propose that the formation of FLIPRs in vivo contributes to the well-established proinflammatory function of platelets and platelet-derived microparticles.
authors.affiliation: From the Laboratory of Clinical Chemistry and Haematology (C.T., H.F.H., R.T.U., C.M., P.G.d.G., M.R.), Laboratory of Experimental Cardiology (C.T., G.P., I.E.H.), and Cell Microscopy Center, Department of Cell Biology (H.F.H.), UMC Utrecht, Utrecht, The Netherlands; UMR-S949 INSERM, EFS-Alsace, Université de Strasbourg, Strasbourg, France (A.E., C.G.); Department of Clinical Chemistry, AMC Amsterdam, Amsterdam, The Netherlands (R.N.); and Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom (R.W.F.).
authors.forename: Claudia
authors.initials: C
authors.lastname: Tersteeg
authors.forename: Harry F
authors.initials: HF
authors.lastname: Heijnen
authors.forename: Anita
authors.initials: A
authors.lastname: Eckly
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.forename: Rolf T
authors.initials: RT
authors.lastname: Urbanus
authors.forename: Coen
authors.initials: C
authors.lastname: Maas
authors.forename: Imo E
authors.initials: IE
authors.lastname: Hoefer
authors.forename: Rienk
authors.initials: R
authors.lastname: Nieuwland
authors.forename: Richard W
authors.initials: RW
authors.lastname: Farndale
authors.forename: Christian
authors.initials: C
authors.lastname: Gachet
authors.forename: Philip G
authors.initials: PG
authors.lastname: de Groot
authors.forename: Mark
authors.initials: M
authors.lastname: Roest
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000166:cytology* / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D020212:Carotid Artery Injuries / Q000276:immunology* / Q000473:pathology; D055252:Cell-Derived Microparticles / Q000276:immunology*; D003599:Cytoskeleton / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology; D064368:Healthy Volunteers; D006801:Humans; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D009504:Neutrophils / Q000166:cytology / Q000276:immunology*; D015539:Platelet Activation / Q000276:immunology; D012039:Regional Blood Flow / Q000276:immunology; D013314:Stress, Mechanical
chemical_list: D002118:Calcium
keywords: flow; microparticles; platelet adhesion; proinflammatory platelets; shear