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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 5380-5392 |
| Number of pages | 13 |
| Journal | Journal of Immunology |
| Volume | 195 |
| Issue number | 11 |
| DOIs | |
| State | Published - Dec 1 2015 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Immunology
Cite this
CD11c/CD18 signals very late antigen-4 activation to initiate foamy monocyte recruitment during the onset of hypercholesterolemia. / Foster, Greg A.; Xu, Lu; Chidambaram, Alagu A.; Soderberg, Stephanie R.; Armstrong, Ehrin J.; Wu, Huaizhu; Simon, Scott I.
In: Journal of Immunology, Vol. 195, No. 11, 01.12.2015, p. 5380-5392.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - CD11c/CD18 signals very late antigen-4 activation to initiate foamy monocyte recruitment during the onset of hypercholesterolemia
AU - Foster, Greg A.
AU - Xu, Lu
AU - Chidambaram, Alagu A.
AU - Soderberg, Stephanie R.
AU - Armstrong, Ehrin J.
AU - Wu, Huaizhu
AU - Simon, Scott I.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.1501077
DO - 10.4049/jimmunol.1501077
M3 - Article
VL - 195
SP - 5380
EP - 5392
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 11
ER -