Apolipoprotein E enhance survival of effector memory regulatory T lymphocytes by regulating caspase-dependent apoptosis and lipid metabolism.

Abstract

Abstract Mechanisms underlying the pleiotropic anti-inflammatory effect of HDL remain incompletely understood. Regulatory T cells (Tregs) are essential for maintaining immune homeostasis in cardiovascular diseases (CVD) and metabolic disorders. We recently show Tregs, particularly effector memory Tregs (emTregs), bind/internalize HDL, which promotes their survival by limiting caspase-dependent apoptosis. As HDL contain a complex mix of proteins and lipids, we investigated which components of HDL mediate this process and found HDL proteins were the most critical. Using reconstituted HDL mimic vesicles containing recombinant HDL proteins and POPC, we found that APOE, but none of the APOA proteins, significantly decreased caspase expression in emTregs similarly to total HDL. Neither APOE nor HDL had any effect on naïve Tregs. APOE-depleted HDL did not rescue emTregs, confirming the critical role of APOE. Because Tregs have distinct metabolic requirements, we next investigated the effect of HDL, APOE3-POPC and APOE-depleted HDL on lipid metabolism in emTregs. APOE3-POPC and HDL significantly increased the concentration of long chain (14:0 20:0) and polyunsaturated fatty acids (FA, 18:3 22:6) in emTregs. Our data also suggested the involvement of de novo FA synthesis, as APOE3-POPC and HDL increased the concentration of palmitate (16:0), the earlier precursor of this pathway. Further, treatment of Tregs with the fatty acid synthase inhibitor C75 abolished HDL survival effect. Our results show that HDL, specifically APOE, promote emTregs survival by regulating de novo FA synthesis and caspase-dependent apoptosis. HDL-APOE levels seem to be dysregulated in CVD and obesity, suggesting this mechanism may contribute to HDL protective role