Chemokine Receptor-6 Promotes B-1 Cell Trafficking to Perivascular Adipose Tissue, Local IgM Production and Atheroprotection

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.

B-1b Cells Have Unique Functional Traits Compared to B-1a Cells at Homeostasis and in Aged Hyperlipidemic Mice With Atherosclerosis

“…Chemokine/chemokine receptors interactions is a major mechanism regulating trafficking of immune cells throughout the body and CCR6 has been shown to regulate B-1 cell mediated atheroprotection in mice (28). In this present study, we found that B-1b cells express significantly more CCR6 than B-1a cells and that CCR6 regulates B-1b cell recruitment to the spleen.…”

“…Notably, canonical pathway analysis showed that, B-1b cells express genes that are involved in CCR6 signaling pathway (Figure 2B). Our recent study demonstrated that CCR6 is highly expressed on splenic total B-1 cells compared to total B-1 cells from PerC (28). Since B-1b cells express high levels of CCR6, this CCR6 may regulate the recruitment of B-1b cells to the spleen.…”

Chemokine Receptor Activation Enhances Memory B Cell Class Switching Linked to IgE Sensitization to Alpha Gal and Cardiovascular Disease

“…As α-gal IgE sensitization has been shown to associate with CAD ( 6 , 7 ), we further explored roles of CCR6 and CXCR4 in cardiovascular disease. Upadhye et al and Srikakulapu et al had previously investigated roles of CCR6 and CXCR4 on B cells in contributing to atherosclerosis ( 33 , 34 ). However, those studies focused on atheroprotective B-1 cells and the role of CCR6 and CXCR4 in boosting anti-inflammatory IgM production.…”

Exploring the Relationship of Perivascular Adipose Tissue Inflammation and the Development of Vascular Pathologies

“…However, there was a decrease in the number of B-1 cells that secrete antiatherosclerotic IgM in ApoE −/− mouse PVAT. This further worsens the atherosclerotic lesion formation in the mouse coronary artery and aorta [ 107 ]. Additionally, microRNA-19b in endothelial cell-derived microparticles promotes atherosclerosis progression in ApoE −/− mice by increasing the secretion of proinflammatory cytokines (IL-6, IL-10, and TNF- α ) and inducing macrophage infiltration in PVAT [ 108 ].…”