| Lipid metabolism and inflammation are closely linked, making them attractive targets for intervention in a variety of diseases, such as atherosclerosis, type 2 diabetes, and autoimmune diseases, as well as for the modulation of the immune response. Cholesterol homeostasis is a tightly regulated process and altering cholesterol levels can severely disturb cell function and tissue homeostasis. ABCG1 is a novel ABC transporter and a primary regulator of cholesterol homeostasis. ABCG1 acts in the plasma membrane to increase the availability of cholesterol to a variety of lipoprotein and nonlipoprotein acceptors while limiting the accumulation of cholesterol in the endoplasmic reticulum. We observe massive lipid accumulation and inflammation in the lungs of Abcg1-/- mice, with an increase in inflammatory cytokines and infiltrating neutrophils, eosinophils, dendritic cells, T cells and B cells. Using bone marrow transplantation studies, we demonstrate that the presence of ABCG1 on macrophages in Abcg1-/- mice is able to rescue both the lipidosis and the inflammatory phenotype. We hypothesize that the absence of ABCG1 affects other cells of the immune system as well, and observe a significant increase in the size and cellularity of the thymus in Abcg1-/- mice. We discover that Abcg1-/- thymocytes and peripheral T cells are hyperproliferative in vivo and in vitro . Abcg1-/- T cells accumulate significant amounts of cholesteryl ester, which results in increased lipid rafts and alters TCR signaling. Abcg1-/- CD4 T cells have enhanced basal phosphorylation levels of both ZAP-70 and ERK1/2. Furthermore, inhibition of ERK phosphorylation in TCR stimulated Abcg1-/- T cells rescues the hyperproliferative phenotype. Our work demonstrates how the absence of ABCG1 in cells of the immune system can severely alter lipid homeostasis and the immune response. A greater understanding of the role of ABCG1 in the immune response could lead to promising new therapeutics to improve the lives of patients suffering from the many diseases defined by disturbances in both lipid metabolism and inflammation. |
