B Cells Under Pressure: How Losing Desmosterol Fuels Atherosclerosis 2260473

Abstract Introduction Atherosclerosis is an inflammatory disease characterized by plaque buildup in vessels. Cholesterol homeostasis is crucial to prevent toxic cholesterol levels, but it is often dysregulated in hyperlipidemic states. Desmosterol, a cholesterol precursor, inhibits macrophage activation. While the impact of cholesterol metabolism on macrophage functions is well-studied, its role in regulating B cell functions remains unclear. Methods We generated atherosclerosis-prone Dhcr24fl/flCd19cre/+Ldlr-/- mice, in which B cells overexpress 24-dehydrocholesterol reductase (DHCR24), an enzyme that converts desmosterol into cholesterol. DHCR24 overexpression depleted desmosterol levels in B cells from Dhcr24fl/flCd19cre/+Ldlr-/- vs Cd19cre/+Ldlr-/- control mice. To test the impact of desmosterol depletion in atherogenesis, Dhcr24fl/flCd19cre/+Ldlr-/- and Cd19cre/+Ldlr-/- mice were fed a high-fat diet (HFD) for 12-16 weeks. Results Desmosterol-depleted B cells from HFD-fed Dhcr24fl/flCd19cre/+Ldlr-/- show increased mitochondrial superoxide production, elevated Ca2+ flux and pSYK in the response to anti-IgM-induced BCR activation vs B cells from Cd19cre/+Ldlr-/- mice. Desmosterol depletion in B cells increased lipid loading and shifted GC formation, which was accompanied by a decline in mitochondrial function of B cells from HFD-fed Dhcr24fl/flCd19cre/+Ldlr-/- mice. Importantly, Dhcr24fl/flCd19cre/+Ldlr-/- mice also increased atherogenesis vs Cd19cre/+Ldlr-/- mice. Conclusion Together, this suggests that desmosterol acts as a suppressive regulator of B cell activation, influencing their functions. This highlights a previously unrecognized role of desmosterol in modulating B cell responses in atherosclerosis. Funding Source n/a Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)