Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of classical monocytes

Abstract

We used a novel approach of cytostatically induced leucocyte depletion and subsequent reconstitution with leucocytes deprived of classical (inflammatory/Gr1hi) or non-classical (resident/Gr1lo) monocytes to dissect their differential role in atheroprogression under high-fat diet (HFD). Apolipoprotein E-deficient (Apoe−/−) mice lacking classical but not non-classical monocytes displayed reduced lesion size and macrophage and apoptotic cell content. Conversely, HFD induced a selective expansion of classical monocytes in blood and bone marrow. Increased CXCL1 levels accompanied by higher expression of its receptor CXCR2 on classical monocytes and inhibition of monocytosis by CXCL1-neutralization indicated a preferential role for the CXCL1/CXCR2 axis in mobilizing classical monocytes during hypercholesterolemia. Studies correlating circulating and lesional classical monocytes in gene-deficient Apoe−/− mice, adoptive transfer of gene-deficient cells and pharmacological modulation during intravital microscopy of the carotid artery revealed a crucial function of CCR1 and CCR5 but not CCR2 or CX3CR1 in classical monocyte recruitment to atherosclerotic vessels. Collectively, these data establish the impact of classical monocytes on atheroprogression, identify a sequential role of CXCL1 in their mobilization and CCR1/CCR5 in their recruitment.

Annexin A1 Counteracts Chemokine-Induced Arterial Myeloid Cell Recruitment

“…In these experiments, the presence of Ac2-26 caused a significant, dose-dependent decrease in myeloid cell adhesion with significant reductions at doses of 10 and 50 μg/mL. With the robust effect of Ac2-26 on CCL5-evoked integrin activation ( Figure 4A and 4B) and the reported importance of CCL5 in arterial recruitment of both neutrophils and monocytes, 13,14 we limited further mechanistic studies to studying the effect of Ac2-26 on CCL5-evoked integrin activation. Here, we find that Ac2-26 dose dependently reduces the affinity for ICAM-1 and VCAM-1 when neutrophils and classical monocytes are activated with CCL5 ( Figure 4C and 4D).…”

CD8 + T Cells Regulate Monopoiesis and Circulating Ly6C high Monocyte Levels in Atherosclerosis in Mice

“…Furthermore, we here observed diminished expression of CCL2 and CXCL1 in atherosclerotic tissue, chemokines that are known to attract monocytes. 22,23,25,26 Reduced chemokine expression in plaque tissue may reflect changes in lesion cellular composition (ie, reduced macrophage content) or reduced chemokine expression by individual plaque cells. In vitro, activated CD8 + T cells promoted expression of CCL2, CXCL1, and CCL5 in macrophages and endothelial cells, and IFN-γ dependently induced CCL2 in macrophages, suggesting that CD8 + T cells may also promote chemokine expression by neighboring cells within plaques.…”

“…Both processes are dependent on specific chemokines. 22 Reduced Ccl2 and Cxcl1 but not Ccl5 transcript levels were observed in the aortic root ( Figure 3A-3C) in mice depleted of CD8 + T cells compared with controls, whereas no changes were noted for adhesion molecules Vcam1, Icam1, Pecam1, and P-selectin between groups (Online Figure VI).…”

Resolving Lipid Mediators Maresin 1 and Resolvin D2 Prevent Atheroprogression in Mice

“…26 To determine lipid mediator levels in atherosclerotic arteries at different stages of atherosclerosis, we subjected snap-frozen aortas from the Apoe −/− mice fed an HFD to liquid chromatography/tandem mass spectrometry analysis (Figure 1). At all 3 time points, we detected inflammatory lipid mediators including Prostaglandins (PGE2, PGD2, PGA1, 15d-PGJ2, and 8iso-PGA2) and Leukotriene B4 (LTB4).…”