CD11c/CD18 Signals Very Late Antigen-4 Activation To Initiate Foamy Monocyte Recruitment during the Onset of Hypercholesterolemia

J Immunol. 2015 Dec 1;195(11):5380-92. doi: 10.4049/jimmunol.1501077. Epub 2015 Oct 30.


Recruitment of foamy monocytes to inflamed endothelium expressing VCAM-1 contributes to the development of plaque during atherogenesis. Foamy CD11c(+) monocytes arise in the circulation during the onset of hypercholesterolemia and recruit to nascent plaque, but the mechanism of CD11c/CD18 and very late Ag-4 (VLA-4) activation and cooperation in shear-resistant cell arrest on VCAM-1 are ill defined. Within 1 wk of the onset of a Western high-fat diet (WD) in apolipoprotein E-deficient mice, an inflammatory subset of foamy monocytes emerged that made up one fourth of the circulating population. These cells expressed ∼3-fold more CD11c/CD18 and 50% higher chemokine receptors than nonfoamy monocytes. Recruitment from blood to a VCAM-1 substrate under shear stress was assessed ex vivo using a unique artery-on-a-chip microfluidic assay. It revealed that foamy monocytes from mice on a WD increased their adhesiveness over 5 wk, rising to twice that of mice on a normal diet or CD11c(-/-) mice fed a WD. Shear-resistant capture of foamy human or mouse monocytes was initiated by high-affinity CD11c, which directly activated VLA-4 adhesion via phosphorylated spleen tyrosine kinase and paxillin within focal adhesion complexes. Lipid uptake and activation of CD11c are early and critical events in signaling VLA-4 adhesive function on foamy monocytes competent to recruit to VCAM-1 on inflamed arterial endothelium.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Ly / metabolism
  • Apolipoproteins E / genetics
  • CD11c Antigen / biosynthesis*
  • CD18 Antigens / biosynthesis*
  • Cell Adhesion
  • Cell Movement / immunology
  • Diet, High-Fat / adverse effects
  • Endothelium, Vascular / immunology
  • Endothelium, Vascular / pathology
  • Enzyme Activation
  • Focal Adhesions
  • Hypercholesterolemia / immunology*
  • Inflammation / immunology*
  • Integrin alpha4beta1 / metabolism*
  • Membrane Microdomains / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microfluidics
  • Monocytes / immunology*
  • Paxillin / metabolism
  • Vascular Cell Adhesion Molecule-1 / metabolism


  • Antigens, Ly
  • Apolipoproteins E
  • CD11c Antigen
  • CD18 Antigens
  • Integrin alpha4beta1
  • Ly-6C antigen, mouse
  • Paxillin
  • Vascular Cell Adhesion Molecule-1