An Allosteric Shift in CD11c Affinity Activates a Proatherogenic State in Arrested Intermediate Monocytes

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.

CITEMO XMBD : A flexible single-cell multimodal omics analysis framework to reveal the heterogeneity of immune cells

“…Another noteworthy finding is that CITEMO multimodal omics identified CD16+ CD45RA+ monocyte which was annotated as NK cells by a previous study ( Fig. 2F ) [ 46 , 47 ]. CD16+ CD45RA+ monocytes are similar to some NK cells, in that they all express CD16 ( Fig.…”

Dietary Effects on Monocyte Phenotypes in Subjects With Hypertriglyceridemia and Metabolic Syndrome

“…Monocyte adhesion assay was performed by using whole blood as previously reported. 23 , 29 , 30 Briefly, coverslips that were coated with recombinant human vascular cell adhesion molecule-1/Fc chimera (R&D Systems) were assembled with a 4-channel polydimethylsiloxane device and kept at 37°C. Heparin-anticoagulated blood (100 μL) was stained with phycoerythrin–anti-CD16 and Alexa Fluor 488–anti-CD14 antibodies at room temperature for 20 minutes.…”

The multifaceted life of macrophages in white adipose tissue: Immune shift couples with metabolic switch

“…Obesity in mice and humans increases monocyte expression of CD11c, 11 a β2 integrin that mediates monocyte adhesion by enhancing the affinity of very late antigen 4 (VLA4) for vascular cell adhesion molecule-1 (VCAM-1) on activated endothelial cells. 30 In patients with hypertriglyceridemia and metabolic syndrome, a short-term intake of high-saturated fat diet compared to lowsaturated fat diet induces higher levels of adhesion molecules, including CD11c, and chemokine receptors, including CCR2, on monocytes. 31 CD11c + or Ly-6C low monocytes in the blood of lean mice, 11,32 it is likely that in response to HFD, increased release of MCP-1 from WAT drives the phenotypic switch of monocytes from CD11c − Ly-6C high to CD11c + or Ly-6C low phenotypes, which facilitates monocyte migration into WAT and subsequent differentiation into macrophages, thereby intensifying inflammation in WAT.…”