Desmosterol plays an atheroprotective role in B cells through B cell subset differentiation and B cell activation

Abstract

Abstract Atherosclerosis is a complex, inflammatory disease associated with lipid accumulation, vascular dysfunction, and inflammatory immune response in the large and medium sized arteries. B cell roles in atherosclerosis are subset specific. Increasing evidence suggests a role for glucose metabolism in shaping the immune response, but less is known about cholesterol metabolism and adaptive immunity. Desmosterol, a precursor of cholesterol in the Bloch cholesterol biosynthesis pathway, serves as a negative regulator of macrophages. To date, the effect of intermediates of cholesterol metabolism on MF functions is an area of intensive study, but little is known about effects of desmosterol in B cell subset-specific functions.We have generated a mouse model with overexpression of 24-dehydrocholesterol reductase (DHCR24), an enzyme that converts desmosterol into cholesterol, specifically in B cells using the cre/flox system crossed with an atherosclerotic mouse model (Dhcr24 fl/flCd19 cre/+Ldlr −/−mice). The deletion of DHCR24 results in reduction of desmosterol specifically in B cells. After fed a Western diet for 12–16 wks aortas were collected to assess lesion formation and spleens were collected to assess B cell subset distribution, activation, and functions by FACs. We demonstrate that overexpression of DHCR24 in B cells leads accelerated lesion formation. This was accompanied by increased BCR-induced B cell activation via the increased Ca2+ flux along with increased FO B cells and decreased MZ B cells. This suggests that desmosterol plays a suppressive role in B cell activation and plays a role in B cell subset differentiation and activation, highlighting a role of desmosterol as a regulator of B cell functions.