Monocyte activation in cardiovascular disease through inflammatory signaling associated with CD11c function

Abstract

Abstract Circulating monocytes are critical in the development and progression of atherosclerotic disease. During disease, prolonged metabolic dysregulation and low-grade inflammation promote monocytosis and subsequent skewing of the circulating monocyte repertoire to favor an expanded frequency of intermediate monocytes (CD14+CD16+CCR2, iMo). Intermediate monocytes display a hallmark upregulation of β2-integrin CD11c/CD18 which works in cooperation with β1-integrin VLA-4 to mediate monocyte capture and firm arrest to endothelial VCAM-1 at sites of disturbed flow at sites of nascent plaque. Notably, the expanded frequency, quantity of iMo CD11c receptors, and CD11c/VLA-4 dependent arrest of iMo to VCAM-1 gauge the severity of cardiovascular disease and are predictive of poor clinical outcome. Using these observations, we sought to examine the functional activity of arrested iMo on a substrate of VCAM-1 under arterial shear stress through the assessment of CD11c outside-in signaling using microfluidic platforms. We find that iMo undergo rapid transmigration (~90sec) at near 100% efficiency following by characteristic ADAM17 dependent shedding of CD16 that coincided with nuclear translocation of NFκβ, and elaboration of intracellular MMP-9 and IL-1β inflammatory molecules. Phenotypic conversion towards activated M1-like macrophages was governed by an allosteric shift in CD11c from high to low affinity on a majority of adherent iMo from CAD and NSTEMI patients, but not those from age-matched healthy subjects. We conclude that CD11c is a molecular biomarker and functionally relevant inflammatory signaling molecule on iMo. Its expression and function provides the most sensitive measure for diagnosing progression of CAD to MI.