title: 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.affiliation: Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616;
authors.forename: Greg A
authors.initials: GA
authors.lastname: Foster
authors.affiliation: Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Lu
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616;
authors.forename: Alagu A
authors.initials: AA
authors.lastname: Chidambaram
authors.affiliation: Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616;
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Soderberg
authors.affiliation: Division of Cardiology, VA Eastern Colorado Healthcare System, University of Colorado School of Medicine, Denver, CO 80220; and.
authors.forename: Ehrin J
authors.initials: EJ
authors.lastname: Armstrong
authors.affiliation: Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX 77030; Section of Leukocyte Biology, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030.
authors.forename: Huaizhu
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616; sisimon@ucdavis.edu.
authors.forename: Scott I
authors.identifier: http://orcid.org/0000-0003-1186-6611
authors.initials: SI
authors.lastname: Simon
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D039521:CD11c Antigen / Q000096:biosynthesis*; D018821:CD18 Antigens / Q000096:biosynthesis*; D002448:Cell Adhesion; D002465:Cell Movement / Q000276:immunology; D059305:Diet, High-Fat / Q000009:adverse effects; D004730:Endothelium, Vascular / Q000276:immunology / Q000473:pathology; D004789:Enzyme Activation; D022001:Focal Adhesions; D006937:Hypercholesterolemia / Q000276:immunology*; D007249:Inflammation / Q000276:immunology*; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044085:Microfluidics; D009000:Monocytes / Q000276:immunology*; D051419:Paxillin / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D001057:Apolipoproteins E; D039521:CD11c Antigen; D018821:CD18 Antigens; D039041:Integrin alpha4beta1; C494192:Ly-6C antigen, mouse; D051419:Paxillin; D019010:Vascular Cell Adhesion Molecule-1