An Allosteric Shift in CD11c Affinity Activates a Proatherogenic State in Arrested Intermediate Monocytes

• Published in: The Journal of immunology (1950) Vol. 205; no. 10; pp. 2806 - 2820
• Main Authors: Hernandez, Alfredo A, Foster, Greg A, Soderberg, Stephanie R, Fernandez, Andrea, Reynolds, Mack B, Orser, Mable K, Bailey, Keith A, Rogers, Jason H, Singh, Gagan D, Wu, Huaizhu, Passerini, Anthony G, Simon, Scott I
• Format: Journal Article
• Language: English
• Published: United States AAI 15.11.2020
• Subjects: Adult; Aged; Allosteric Regulation - immunology; Aorta - cytology; Case-Control Studies; CD11c Antigen - metabolism; Cell Culture Techniques; Cell Line; Cell Membrane - metabolism; Coronary Artery Disease - blood; Coronary Artery Disease - immunology; Coronary Artery Disease - surgery; Coronary Vessels - cytology; Coronary Vessels - immunology; Endothelial Cells - cytology; Endothelial Cells - immunology; Endothelial Cells - metabolism; Endothelium, Vascular - immunology; Endothelium, Vascular - metabolism; Female; Humans; Innate Immunity and Inflammation; Integrin alpha4beta1 - metabolism; Lab-On-A-Chip Devices; Male; Microfluidic Analytical Techniques - instrumentation; Middle Aged; Monocytes - immunology; Non-ST Elevated Myocardial Infarction - blood; Non-ST Elevated Myocardial Infarction - immunology; Non-ST Elevated Myocardial Infarction - surgery; Percutaneous Coronary Intervention; Recombinant Proteins - immunology; Recombinant Proteins - metabolism; Transendothelial and Transepithelial Migration - immunology; Vascular Cell Adhesion Molecule-1 - immunology; Vascular Cell Adhesion Molecule-1 - metabolism
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.2000485

Intermediate monocytes (iMo; CD14+CD16+) increase in number in the circulation of patients with unstable coronary artery disease (CAD), and their recruitment to inflamed arteries is implicated in events leading to mortality following MI. Monocyte recruitment to inflamed coronary arteries is initiated by high affinity β2-integrin (CD11c/CD18) that activates β1-integrin (VLA-4) to bind endothelial VCAM-1. How integrin binding under shear stress mechanosignals a functional shift in iMo toward an inflammatory phenotype associated with CAD progression is unknown. Whole blood samples from patients treated for symptomatic CAD including non-ST elevation MI, along with healthy age-matched subjects, were collected to assess chemokine and integrin receptor levels on monocytes. Recruitment on inflamed human aortic endothelium or rVCAM-1 under fluid shear stress was assessed using a microfluidic-based artery on a chip (A-Chip). Membrane upregulation of high affinity CD11c correlated with concomitant activation of VLA-4 within focal adhesive contacts was required for arrest and diapedesis across inflamed arterial endothelium to a greater extent in non-ST elevation MI compared with stable CAD patients. The subsequent conversion of CD11c from a high to low affinity state under fluid shear activated phospho-Syk– and ADAM17-mediated proteolytic cleavage of CD16. This marked the conversion of iMo to an inflammatory phenotype associated with nuclear translocation of NF-κB and production of IL-1β+. We conclude that CD11c functions as a mechanoregulator that activates an inflammatory state preferentially in a majority of iMo from cardiac patients but not healthy patients.