An allosteric shift in cd11c affinity activates a proatherogenic state in arrested intermediate monocytes

Alfredo A. Hernandez, Greg A. Foster, Stephanie R. Soderberg, Andrea Fernandez, Mack B. Reynolds, Mable K. Orser, Keith A. Bailey, Jason H. Rogers, Gagan D. Singh, Huaizhu Wu, Anthony G. Passerini, Scott I Simon

Research output: Contribution to journalArticlepeer-review

Abstract

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 b2-integrin (CD11c/CD18) that activates b1-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-kB and production of IL-1b+. 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.

Original languageEnglish (US)
Pages (from-to)2806-2820
Number of pages15
JournalJournal of Immunology
Volume205
Issue number10
DOIs
StatePublished - Nov 15 2020
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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