FLow-Induced PRotrusions (FLIPRs): A Platelet-Derived Platform for the Retrieval of Microparticles by Monocytes and Neutrophils
Rationale: 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: Study the dynamic process that leads to the formation of procoagulant and pro-inflammatory platelets under physiological flow.
Methods and 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 up to 250 υm. 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/PSGL-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: Formation of long platelet membrane extensions, such as 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 pro-inflammatory function of platelets and platelet-derived microparticles.
- Received August 5, 2013.
- Revision received January 7, 2014.
- Accepted January 8, 2014.