The Role of Desmosterol in Regulating B1a Cell Functions in Atherosclerosis - Summary Atherosclerosis causes 25% of global deaths, with the immune response playing a key regulatory role in this pathology. The functions of B cells vary between subsets, and as such, their impact on atherosclerosis is B cell subset-specific. Follicular (FO) and Innate response activator (IRA) B cells accelerate atherogenesis, while marginal zone (MZ) B cells and B1 cells protect against the disease. While B cell contribution to atherosclerosis is widely recognized, the metabolic pathways governing B cell subset function in atherogenesis remain unclear. B cells undergo significant shifts in metabolism during development, differentiation, and activation. Emerging evidence suggests that cholesterol metabolism is integral in the metabolic reprogramming of B cells, which, together with proper mitochondrial functions and autophagy, maintain metabolic balance and functions of B cells. Our data reveal a reprogramming of B1 cell metabolism and mitochondrial activity in atherosclerosis. We show that chronic exposure to hypercholesterolemia causes the accumulation of desmosterol, the last biosynthetic precursor of cholesterol in the Bloch cholesterol biosynthesis pathway, in B cells. When desmosterol is selectively depleted in the B cells of Ldlr-/- mice, atherosclerosis is augmented with concomitant alterations in B cell effector roles and complex-1 dependent mitochondrial functions. Importantly, B1a cells are the most sensitive subset to desmosterol depletion, demonstrated by high reactive oxygen species production, altered lipid accumulation, reduced proliferation, and diminished IgM production. Here, we hypothesize that desmosterol accumulation supports oxidative phosphorylation, autophagy, self-renewal, and Ab production in B1a cells by positively regulating Complex-I-dependent mitochondrial functions, thereby reinforcing B1a cell suppressive immune role in atherosclerosis. To test this hypothesis, we propose two specific aims. Aim 1 will focus on the impact of atherosclerosis and associated hypercholesterolemia on metabolism, autophagy, and mitochondria in B1a cells and test the role of desmosterol in these processes. We will examine B1 cells from healthy subjects and patients with atherosclerosis and hypercholesterolemia, as well as B1a cells isolated from the Western Diet (WD) or Chow Diet (CD) fed Ldlr-/- mice. Aim 2 will investigate how desmosterol depletion impairs B1a cell functions and immune response by disrupting Complex-I-dependent mitochondrial functions, leading to increased atherosclerosis. Overall, this project will offer novel and important insights into how sterol metabolism affects the quality and longevity of B1a cell-dependent immune responses in atherosclerosis.
