Abstract
Chemokine receptor-6 (CCR6) mediates immune cell recruitment to inflammatory sites and has cell type-specific effects on diet-induced atherosclerosis in mice. Previously we showed that loss of CCR6 in B cells resulted in loss of B cell-mediated atheroprotection, although the B cell subtype mediating this effect was unknown. Perivascular adipose tissue (PVAT) harbors high numbers of B cells including atheroprotective IgM secreting B-1 cells. Production of IgM antibodies is a major mechanism whereby B-1 cells limit atherosclerosis development. Yet whether CCR6 regulates B-1 cell number and production of IgM in the PVAT is unknown. In this present study, flow cytometry experiments demonstrated that both B-1 and B-2 cells express CCR6, albeit at a higher frequency in B-2 cells in both humans and mice. Nevertheless, B-2 cell numbers in peritoneal cavity (PerC), spleen, bone marrow and PVAT were no different in ApoE−/−CCR6−/− compared to ApoE−/−CCR6+/+ mice. In contrast, the numbers of atheroprotective IgM secreting B-1 cells were significantly lower in the PVAT of ApoE−/−CCR6−/− compared to ApoE−/−CCR6+/+ mice. Surprisingly, adoptive transfer (AT) of CD43− splenic B cells into B cell-deficient μMT−/−ApoE−/− mice repopulated the PerC with B-1 and B-2 cells and reduced atherosclerosis when transferred into ApoE−/−CCR6+/+sIgM−/− mice only when those cells expressed both CCR6 and sIgM. CCR6 expression on circulating human B cells in subjects with a high level of atherosclerosis in their coronary arteries was lower only in the putative human B-1 cells. These results provide evidence that B-1 cell CCR6 expression enhances B-1 cell number and IgM secretion in PVAT to provide atheroprotection in mice and suggest potential human relevance to our murine findings.
Highlights
Atherosclerosis is well-recognized as a chronic inflammatory disease of arteries and plaque rupture is the primary underlying cause of cardiovascular events
We have recently shown that the Perivascular adipose tissue (PVAT) harbors both B-1 and B2 B cell subtypes in young ApoE−/− mice and these local B1 cells can be induced to proliferate by cytokines [16] and produce atheroprotective IgM antibodies locally [17]
We demonstrate that atheroprotective effects of CD43− splenocytes in apolipoprotein-E deficient (ApoE−/−)sIgM−/− mice are chemokine receptor 6 (CCR6)-dependent and require the cells to be capable of secreting IgM implicating PVAT trafficking of B-1 cells as a potentially important atheroprotective mechanism
Summary
Atherosclerosis is well-recognized as a chronic inflammatory disease of arteries and plaque rupture is the primary underlying cause of cardiovascular events. Atherosclerosis develops when low density lipoproteins (LDL) enter the subendothelial layer of the artery wall and become oxidized. Products of oxidized lipids are highly reactive and modify self-molecules, thereby generating oxidation-specific epitopes (OSE) that are recognized by receptors of the immune system, including scavenger receptors on macrophages leading to foam cell formation. Oxidized LDL and foam cells promote inflammatory cytokine production and induce the expression of cell adhesion molecules on endothelial cells. Treatments that deplete predominantly B-2 cells such as anti-CD20 monoclonal antibody and B-cell activating factor receptor (BAFFR) deficiency attenuated atherosclerosis development in apolipoprotein-E deficient (ApoE−/−) and low-density lipoprotein receptor deficient (LdlR−/−) mice maintained on Western diet (WD) [5, 6, 8, 9]. IgM can block the uptake of oxidized LDL by macrophages [12] and, immunization to boost IgM to OSE resulted in atheroprotection [13]
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