Abstract
Several studies address the role of CD11c + monocytes in the exacerbation of atherosclerosis through the maintenance of macrophages, notably foam cells, however this cell type remains elusive in the context of human atherosclerosis. Intermediate monocytes (CD14+CD16+, Mon2) have a high degree of potential participation in atherosclerosis through the upregulation of membrane β2-integrin CD11c/CD18 expression that functionally orchestrates their recruitment to VCAM-1 activating VLA-4 leading to focal clustering and shear resistant arrest. Both Mon2 frequency and CD11c expression remain critical factors associated with the extent of coronary artery disease (CAD) related to persistent inflammation, plaque growth and destabilization, myocardial infarction and morbidity. Understanding dynamic alteration of Mon2 CD11c and its function in promoting macrophage accumulation in plaques that exacerbate and progress atherosclerotic disease progression toward myocardial infarction remains undetermined. In this study, we investigated the activation status of circulating Mon2 in patients experiencing non-ST myocardial infarction (NSTEMI) compared to those undergoing angiography in the cardiac clinic. Mon2 activation status and CD11c function was gauged using flow cytometry and real-time microfluidics using an Artery-on-a-Chip (A-Chip) device. Circulating Mon2 upregulated CD11c receptors to the greatest extent in patients experiencing myocardial infarct that increase with recurrence and lead to enhanced CD11c dependent capture on VCAM-1 relative to patients being treated in the cardiac clinic. Arrest on VCAM-1 under shear flow resulted in time-dependent phenotypic alteration including the loss of CD16 over 45 min and was dependent on atherosclerotic disease but independent of NSTEMI and involved CD11c outside-in signaling. A shift from a high to low affinity state of CD11c triggered the translocation of several activation and differentiation markers such as NfKB, and upregulation of MMP-9 associated with an M1 phenotype. CD11c receptor number and subsequent signaling provides a potential target for intervention of atherogenesis by altering Mon2 differentiation potential and inflammatory capacity.
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