NR4A1 Deletion in Marginal Zone B Cells Exacerbates Atherosclerosis in Mice-Brief Report.

Meritxell Nus,Christoph J Binder,Frederic Geissmann,Tian X Zhao,Ziad Mallat,Maria Galan,Andrew P Sage,Dimitrios Tsiantoulas,James Harrison,Leanne Masters,Nichola Figg,Laia Cros-Brunsó,Gemma Basatemur

doi:10.1161/atvbaha.120.314607

Abstract

NR4A orphan receptors have been well studied in vascular and myeloid cells where they play important roles in the regulation of inflammation in atherosclerosis. NR4A1 (nerve growth factor IB) is among the most highly induced transcription factors in B cells following BCR (B-cell receptor) stimulation. Given that B cells substantially contribute to the development of atherosclerosis, we examined whether NR4A1 regulates B-cell function during atherogenesis. Approach and Results: We found that feeding Ldlr-/- mice a Western diet substantially increased Nr4a1 expression in marginal zone B (MZB) cells compared with follicular B cells. We then generated Ldlr-/- mice with complete B- or specific MZB-cell deletion of Nr4a1. Complete B-cell deletion of Nr4a1 led to increased atherosclerosis, which was accompanied by increased T follicular helper cell-germinal center axis response, as well as increased serum total cholesterol and triglycerides levels. Interestingly, specific MZB-cell deletion of Nr4a1 increased atherosclerosis in association with an increased T follicular helper-germinal center response but without any impact on serum cholesterol or triglyceride levels. Nr4a1-/- MZB cells showed decreased PDL1 (programmed death ligand-1) expression, which may have contributed to the enhanced T follicular helper response. Our findings reveal a previously unsuspected role for NR4A1 in the atheroprotective role of MZB cells.

Highlights

Meritxell Nus, Gemma Basatemur, Maria Galan, Laia Cros-Brunsó, Tian X
APPROACH AND RESULTS: We found that feeding Ldlr−/− mice a Western diet substantially increased Nr4a1 expression in marginal zone B (MZB) cells compared with follicular B cells
Complete B-cell deletion of Nr4a1 led to increased atherosclerosis, which was accompanied by increased T follicular helper cell–germinal center axis response, as well as increased serum total cholesterol and triglycerides levels

Summary

Methods

The data that support the findings of this study are available from the corresponding author upon reasonable request. Recipient Ldlr−/−; Cd79aCre/+; RBPflox/flox male and female mice were partially irradiated (1 single dose of 4 Gy) and injected intravenously with BM from Nr4a1−/− or WT C57Bl/6J male and female mice, respectively, which we expected to result in reconstitution of MZB cell compartment with cells coming from the donors (Nr4a1−/− or WT), while the rest of immune cells (including FOB, T, myeloid, etc) would be mostly from the recipient. To validate this partial irradiation model, we used the CD45 (cluster of differentiation 45) congenic lineage tracing system.

Results

Discussion

Conclusion