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

Abstract

Objective: 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 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 expression, which may have contributed to the enhanced T follicular helper response. Conclusions: Our findings reveal a previously unsuspected role for NR4A1 in the atheroprotective role of MZB cells.

Functional Role of B Cells in Atherosclerosis

“…In contrast, Nur77 was significantly decreased in FO B cells, implying that FO B cells are encountering less self-antigens in atherosclerosis or that B cell activation is regulated differentially in this B cell subset. In line with that, Nus et al found that FO B cells upregulated ICOSL, a major inducer of Tfh-cell differentiation in atherosclerosis [ 55 ], which is facilitated by lower BCR signal strength [ 57 ]. Differentiation into short-lived plasma cells (SLPC) or GC B cells is also determined by a BCR signal strength [ 58 , 59 , 60 , 61 ].…”

“…A recent study by Nus and colleagues further highlighted a potential role for a BCR-dependent B cell differentiation and activation in atherosclerosis [ 55 ]. Nur77 (nerve growth factor IB) is a highly induced transcription factor upon BCR engagement in B cells, reflecting the levels of BCR-dependent B cell activation.…”

“…MZ B cells are the smallest subset of B2 B cells and their specialized location in the outer white pulp of the spleen allows them to respond rapidly to bloodborne pathogens and other T-cell-independent antigens, typically through TLR signaling [ 45 , 102 ]. So far, accumulating data indicate that MZ B cells play a protective role in atherosclerosis likely via two different pathways: suppression of Tfh cells and production of protective IgM Abs [ 55 ]. Mechanistically, atherosclerotic conditions upregulate the cAMP-dependent transcription factor ATF3, which induces the surface expression of PDL-1 on MZ B cells, thereby suppressing Tfh cell motility, Tfh differentiation and abundance, and proatherogenic Tfh cell-mediated responses [ 56 ].…”

Novel NR4A1 Arg293Ser Mutation in Patients With Familial Crohn’s Disease

“…In an in vitro model, Nr4a1 deletion in B2 cells increased atherosclerosis and was associated with increased T follicular helper cell-Germinal Center response and NR4A1 expression in Marginal Zone B cells regulating PD-L1 expression, limiting the T follicular helper cell-Germinal Center response and protecting from atherosclerosis (19). The NR4A1 expression was elevated in human osteoarthritis cartilage and in an in vitro osteoarthritis model, which could be blocked by the NF-ĸB signal inhibitor JSH23 (20).…”

Transcriptional Profiling of Monocytes Deficient in Nuclear Orphan Receptors NR4A2 and NR4A3 Reveals Distinct Signalling Roles Related to Antigen Presentation and Viral Response

“…NR4A expression is associated with a number of pathologies e.g. arthritis (3)(4)(5)(6), T cell dysfunction (7), fibrosis (8), atherosclerosis (9) and cancer (10,11). Furthermore, over the last decade NR4A receptors have become targets for pharmacological intervention.…”