Abstract 408: ApoE Regulation of Hematopoiesis Suppresses Atherosclerosis by Reducing Adaptive Immunity in Hyperlipidemic Mice

Background and Purpose: Apolipoprotein (apo) E suppresses atherosclerosis by exerting a profound control over cells of the innate immune system including monocytes and macrophages. In mice with hyperlipidemia, apoE also prevents an exaggerated proliferation of hematopoietic stem and progenitor cells (HSPC) to further limit the expansion of innate immune cells. However, apoE’s control over hematopoiesis and its subsequent shaping of adaptive immunity remains unexplored. Methods: We explored this question by studying HypoE mice deficient in the LDL receptor ( Apoe h/h Ldlr –/– mice) that display plasma lipid levels similar to those of Apoe -/- Ldlr -/- mice when fed a chow diet, but accumulate apoE in plasma and display reduced atherosclerosis. Populations of HSPC were examined in the bone marrow (BM) and spleen, while populations of mature immune cells and their levels of cellular activation were examined in the blood, spleen, lymph nodes and aorta of twenty-week-old mice. Results: Our findings show that apoE suppressed the expansion of HSPC in both the spleen and BM of Apoe h/h Ldlr -/- mice, which remained similar to levels seen in normal wildtype mice. Specifically, in the spleens of Apoe h/h Ldlr -/- mice, apoE reduced the expansion of a population of multi-potent progenitors termed MPP4 responsible for lineages of lymphoid cells. Accordingly, Apoe h/h Ldlr -/- mice displayed smaller spleens and lymph nodes that contained fewer myeloid- and lymphoid-derived leukocytes compared to Apoe -/- Ldlr -/- mice. The spleens and lymph nodes of Apoe h/h Ldlr -/- mice had a higher percentage of T cells that displayed a naïve phenotype, while the percentage of effector T cells was decreased and produced 50% less IFN-γ. Dendritic cells isolated from spleens of Apoe h/h Ldlr -/- mice showed reduced levels of CD86 that plays a key role in T cell activation. Digested aortas of Apoe h/h Ldlr -/- mice revealed a decrease in both T cell and myeloid cell number that also displayed a lower percentage of the pro-inflammatory CD11b + subtype but a higher percentage of the anti-inflammatory CD103 + subtype. Conclusion: Collectively, our findings show that the control of hematopoiesis exerted by apoE results in reduced adaptive immunity to suppress atherosclerosis in hyperlipidemic mice.