CD45-dependent regulation of B cell receptor signaling in atherosclerosis

Abstract

Abstract Atherosclerosis is an inflammatory disease of the large and medium size arteries that is characterized by deposition of oxidized lipids within the vessel. While specific antigens are not well characterized, data show that the immune response is involved in atherogenesis. The role of B cells in atherosclerosis is B cell specific: FO B cells are proatherogenic, while B1 and MZ B cells serve as protective. B cell development, activation, and differentiation is dependent on B cell receptor signaling while important costimulatory molecules, like CD45, assist in the initial propagation of signal. To date, it is unknown how regulation of BCR signaling by CD45 impacts activation and functions of B cells in atherosclerosis. We took advantage of transgenic mice that express low levels of CD45 (CD45L/L) and examined the phenotype of CD45L/L B cells. We demonstrate that low expression of CD45 leads to attenuated BCR-induced B cell activation via the reduced Ca2+ flux and phosphorylation of ERK, BTK, and SYK kinase, while favoring MZ and B1 B cell differentiation in homeostatic conditions. To test the effects of B cells expressing low levels of CD45 in atherosclerosis, we performed adoptive transfer of CD45L/L or WT B cells into B cell-deficient atherosclerotic prone mice. After 23–28 wks of western diet feeding, the CD45L/L vs WT B cell recipients had reduced lesion formation accompanied by increased MZ B cells and decreased germinal center formation. This suggests that attenuation of BCR signaling through CD45 affects B cell subset differentiation and activation and highlight a potential role of BCR-related signaling in regulation of immunity in atherosclerosis.