B-Cell–Specific CXCR4 Protects Against Atherosclerosis Development and Increases Plasma IgM Levels

Over the last years, studies focusing on the role of B cells in atherosclerosis¹ have revealed that this cell subset can have both pro- and antiatherosclerotic properties depending on the specific subset and method of targeting. Recently, Upadhye et al² found that the chemokine receptor CXCR4 (C-X-C chemokine receptor type 4) plays a crucial role in B-cell localization and IgM production. A clear human validation focussing on CXCR4-expressing B1 cells in relation to human plaque burden could be demonstrated. However, an unambiguous causal role for CXCR4 on B cells in atherosclerosis development remained elusive.

Using female B-cell–specific Cxcr4-deficient mice on Apoe^−/− background, we could show that after 12 weeks of Western diet feeding (Figure), in line with the findings by Upadhye et al,² blood and especially bone marrow B1 levels were decreased, while B2 levels did not change (data not shown). This coincided with a striking decrease in plasma IgM levels, while plasma CXCL12 (C-X-C motif chemokine 12) and lipid levels remained unchanged. As it has already been demonstrated that B1 cells mediate their atheroprotective effects via IgM secretion,^3,4 we subsequently analyzed lesion formation in these mice. As expected based on the decreased B1 cell and IgM plasma levels, atherosclerotic lesion size was significantly increased in the aortic root and arch of B-cell–specific Cxcr4-deficient mice. Interestingly, preliminary results revealed no differences in lesion size and IgM levels in male mice (data not shown), highlighting the importance of sex hormones. Additionally, plaque macrophage content was significantly increased, while smooth muscle cell content, necrotic core, and collagen area remained unchanged upon B-cell Cxcr4 deficiency. Overall, these results suggest that it is highly plausible that the atherosclerotic effects observed upon B-cell Cxcr4 deficiency are primarily caused by a B-cell–mediated decrease in IgM levels.

We perceive our data as the missing link between Upadhye et al² who have not analyzed atherosclerotic lesion development in B-cell–specific CXCR4-deficient animals but clearly show the importance of CXCR4 expression on B1 cells in controlling IgM titres and studies showing the importance of B1 cell–derived IgM in atheroprotection^3,4 but no causative explanation of its regulation.

In conclusion, our results clearly demonstrate a causal role for B-cell CXCR4 in atheroprotection, which coincided with increased protective IgM titres.