Abstract 548: Scavenger Receptor Bi-deficiency-induced Hypercholesterolemia Impairs Lymphocyte Homeostasis
Objective-Deficiency in Scavenger receptor BI (SR-BI), an HDL receptor, leads to a specific HDL-c-elevated hypercholesterolemia and impairs lymphocyte homeostasis in mice. However, how SR-BI-deficiency-induced hypercholesterolemia contributes to the adaptive immunity defects remains unknown.
Hypothesis-SR-BI-deficiency-induced hypercholesterolemia leads to the impaired lymphocyte homeostasis.
Methods and Results-We utilized two animal models combined with cell culture to test our hypothesis. First, in a high fat/high cholesterol (HF) diet mouse model (n>10 per group), we introduced a 2-fold increase in plasma cholesterol concentration. For HF diet SR-BI+/+ mice, the increased cholesterol was distributed in VLDL/LDL fraction, but the lymphocyte homeostasis was not affected. In contrast, for HF diet SR-BI-/- mice, in addition to VLDL/LDL-c, HDL-c was also further elevated. These mice exhibited marked disruption in lymphocyte homeostasis, as characterized by a 1.6-fold increase in T cell number (2.7-fold vs SR-BI+/+ group), a 2.1-fold increase in B cell number (4.2-fold vs SR-BI+/+ group), exacerbated T cell activation and further accelerated B cell proliferation compared with control diet SR-BI-/- mice. Then, in a bone marrow transplantation model (n=5~6 per group), we found that HF diet SR-BI-/- recipients whether receiving SR-BI+/+ or SR-BI-/- BMCs displayed higher lymphocyte numbers, greater lymphocyte activation and more lymphocyte proliferation than respective HF diet SR-BI+/+ controls, indicating that non-hematopoietic SR-BI-deficiency environment was the dominant factor leading to the impaired adaptive immunity. Finally, in a series of in vitro lymphocyte activation experiments (n=4 per group, repeated twice), we found that HDL from control diet or HF diet SR-BI+/+ mice exhibited an inhibitory effect on T cell or B cell proliferation under TCR or BCR stimulation, but HDL from HF diet SR-BI-/- mice completely lost that function, indicating that the dysfunctional HDL in HF diet SR-BI-/- mice was responsible for impaired lymphocyte homeostasis.
Conclusion-The SR-BI-deficiency-induced hypercholesterolemia is the leading factor for impaired lymphocyte homeostasis in SR-BI-/- mice.
- © 2013 by American Heart Association, Inc.