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

Area of Science:

• Immunology
• Cardiovascular Biology
• Cellular Mechanobiology

Background:

• Intermediate monocytes (iMo) increase in unstable coronary artery disease (CAD) and contribute to mortality post-myocardial infarction (MI).
• Monocyte recruitment involves integrins like CD11c/CD18 and VLA-4 binding to VCAM-1 on inflamed endothelium.
• The mechanosignaling pathways driving iMo phenotype shifts under shear stress in CAD remain unclear.

Purpose of the Study:

• To investigate how integrin binding under shear stress mechanosignals a functional shift in iMo toward an inflammatory phenotype in CAD patients.
• To elucidate the role of CD11c in regulating iMo inflammatory responses in the context of symptomatic CAD.

Main Methods:

• Analysis of chemokine and integrin receptor levels on monocytes from CAD patients and healthy controls.
• Microfluidic 'artery on a chip' model assessing monocyte recruitment on inflamed endothelium or VCAM-1 under fluid shear stress.
• Assessment of signaling pathways including phospho-Syk, ADAM17, and NF-κB activation.

Main Results:

• High-affinity CD11c upregulation and VLA-4 activation were crucial for iMo arrest and diapedesis, particularly in non-ST elevation MI patients.
• Shear stress induced a conversion of CD11c from high to low affinity, triggering CD16 cleavage.
• This process led to iMo inflammatory phenotype conversion, marked by NF-κB translocation and IL-1β production, predominantly in cardiac patients.

Conclusions:

• CD11c acts as a mechanoregulator, activating an inflammatory iMo phenotype in a majority of cardiac patients but not healthy individuals.
• This CD11c-mediated pathway is a key driver of monocyte-driven inflammation in CAD progression.
• Findings highlight a novel mechanism linking mechanical forces to immune cell phenotype in cardiovascular disease.