Dampening the B Cell Response, a modified lipid story.

Abstract

Abstract Atherosclerosis is a multifaceted chronic inflammatory disease characterized by the accumulation of modified low density lipoproteins (mLDL) and immune cells in the aortic wall leading to vascular dysfunction. Uptake of mLDL by macrophages (MF) and the formation of foam cells are key events in the induction of atherosclerosis. Our data shows that B cells can also uptake acetylated and oxidized LDL (acLDL and oxLDL, respectively), but the functional consequences of this uptake are currently not well-understood. The transcriptional profiles of sorted B cells that took up acLDL in vivo by RNAseq suggests that acLDL+ B cells assume a role distinct from MF, and reduces activation. Upon mLDL uptake, B cells dampen activating signaling molecule such as SYK, ERK, and BTK, but upregulate inhibitory signaling molecules such as phospho-Lyn (Tyr507). Importantly, the uptake of mLDL affects the ability of B cells to be activated both in vivo and in vitro. mLDL+ B cells mobilize less intracellular calcium in response to B cell receptor cross-linking. Additionally, after mLDL uptake, B cells are less efficient in response to TI-2 antigen DNP-Ficoll and B cells produce significantly lower levels of anti DNP-IgM Abs after the immunization. Upon several TLR stimulations B cells that took up acLDL also produce significantly less proinflammatory cytokines (IFN-g, IL-6). Together the results suggest that mLDL uptake by B cells results in an upregulation of threshold for B cell activation in pro-inflammatory atherosclerosis-prone conditions. Thus, the uptake of mLDL by B cells may play an unexpected protective role in atherosclerosis.