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

Abstract

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.

• Authors: Greg A Foster, Lu Xu, Alagu A Chidambaram, Stephanie R Soderberg, Ehrin J Armstrong, Huaizhu Wu, Scott I Simon
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 195 Issue 11 Pg. 5380-92 (Dec 01 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 26519532 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 by The American Association of Immunologists, Inc.

Chemical References

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

Topics

• 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, 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)