Novel whole blood assay for phenotyping platelet reactivity in mice identifies ICAM-1 as a mediator of platelet-monocyte interaction

British Heart Foundation (PG/12/68/29779 and PG/14/48/30916) and the Wellcome Trust (101604/Z/13/Z to SN and TW, and 098291/Z/12/Z to S.N)

¿Antidepresivos glutamatérgicos? las sorprendentes propiedades antidepresivas de la quetamina

This work has been financed by the SAF2007-62378 project and by the Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)Peer Reviewe

Contribution of Platelet CX(3)CR1 to Platelet-Monocyte Complex Formation and Vascular Recruitment During Hyperlipidemia

Objective— The chemokine receptor CX 3 CR1 is an inflammatory mediator in vascular diseases. On platelets, its ligation with fractalkine (CX 3 CL1) induces platelet activation followed by leukocyte recruitment to activated endothelium. Here, we evaluated the expression and role of platelet-CX 3 CR1 during hyperlipidemia and vascular injury. Methods and Results— The existence of CX 3 CR1 on platelets at mRNA and protein level was analyzed by RT-PCR, quantitative (q)PCR, FACS analysis, and Western blot. Elevated CX 3 CR1 expression was detected on human platelets after activation and, along with increased binding of CX 3 CL1, platelet CX 3 CR1 was also involved in the formation of platelet–monocyte complexes. Interestingly, the expression of CX 3 CR1 was elevated on platelets from hyperlipidemic mice. Accordingly, CX 3 CL1-binding and the number of circulating platelet–monocyte complexes were increased. In addition, CX 3 CR1 supported monocyte arrest on inflamed smooth muscle cells in vitro, whereas CX 3 CR1-deficient platelets showed decreased adhesion to the denuded vessel wall in vivo. Conclusion— Platelets in hyperlipidemic mice display increased CX 3 CR1-expression and assemble with circulating monocytes. The formation of platelet–monocyte complexes and the detection of platelet-bound CX 3 CL1 on inflamed smooth muscle cells suggest a significant involvement of the CX 3 CL1–CX 3 CR1 axis in platelet accumulation and monocyte recruitment at sites of arterial injury in atherosclerosis. </jats:sec

Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of classical monocytes

We used a novel approach of cytostatically induced leucocyte depletion and subsequent reconstitution with leucocytes deprived of classical (inflammatory/Gr1(hi)) or non-classical (resident/Gr1(lo)) monocytes to dissect their differential role in atheroprogression under high-fat diet (HFD). Apolipoprotein E-deficient (Apoe(−/−)) mice lacking classical but not non-classical monocytes displayed reduced lesion size and macrophage and apoptotic cell content. Conversely, HFD induced a selective expansion of classical monocytes in blood and bone marrow. Increased CXCL1 levels accompanied by higher expression of its receptor CXCR2 on classical monocytes and inhibition of monocytosis by CXCL1-neutralization indicated a preferential role for the CXCL1/CXCR2 axis in mobilizing classical monocytes during hypercholesterolemia. Studies correlating circulating and lesional classical monocytes in gene-deficient Apoe(−/−) mice, adoptive transfer of gene-deficient cells and pharmacological modulation during intravital microscopy of the carotid artery revealed a crucial function of CCR1 and CCR5 but not CCR2 or CX(3)CR1 in classical monocyte recruitment to atherosclerotic vessels. Collectively, these data establish the impact of classical monocytes on atheroprogression, identify a sequential role of CXCL1 in their mobilization and CCR1/CCR5 in their recruitment