ACKR3 is important for splenic B2 cell maturation into plasma cells. B cells play a dual role in atherosclerosis as IgM-producing B1 cells are atheroprotective while B2 cells are pro-atherosclerotic. Here we investigate the role of ACKR3 specific knockout on B cells in the development of atherosclerosis and hypothesise that its cell-specific loss of function will reduce the development of the disease.

The role of ACKR3 expression is studied on an atherosclerotic mouse model (Apoe-/-) with cell-specific ACKR3 loss of function on B cells (CD19Cre+ ACKR3fl/fl Apoe-/-). These mice were fed either 4 (B cell-ACKR3 KO n=15, control n=20) or 12 weeks (B cell-ACKR3 KO n=17, control n=20) of Western Diet (WD) and atherosclerotic lesion characteristics, differential B cell subpopulations and plasma antibody titers were analysed. Statistical analysis was done using unpaired, two-sided t-test.

After 12 weeks of WD, mice lacking ACKR3 showed a significant decrease of aortic and root lesions. In addition, foam cells number and necrotic core size were significantly decreased after 12 weeks WD. The atheroprotective IgM content in the plaque was increased both after 4 and 12 weeks WD. Loss of B cell ACKR3 lead also to an increase of atheroprotective B1 cells in the blood and bone marrow (BM) compared with controls (ACKR3fl/fl Apoe-/-). On the other hand, atherogenic B2 cell numbers in the blood and BM as well as pro-atherogenic plasma cells in the BM, lymph node and spleen were significantly reduced. Additionally, atherogenic plasma titers of IgG subclasses such as IgG1, IgG2a and IgG2b are decreased.

Our data suggest that cell-specific loss of ACKR3 on B cells has an atheroprotective role in atherosclerosis by decreasing pro-atherogenic B2 cells as well as plasma cells and pro-atherogenic antibody production while increasing atheropretective B1 cells and IgM antibodies leading to a reduction of foam cells and necrotic core area in the lesions. Further in vitro, we will investigate the role of B cell specific ACKR3 in B cell activation as well as B cell migration towards chemoattractants. In addition, splenic B cell-ACKR3 deficiency is under investigation at a single cell level to unravel differential transcriptomics between the WT and KO mice under Western type Diet.