The anti-inflammatory nature of HDL in macrophages is mediated by ATF3

Elevated plasma levels of High Density Lipoprotein (HDL) are associated with decreased risk of cardiovascular disease (CVD). The protective role of HDL in atherosclerosis has been attributed primarily to its ability to remove excess cholesterol from lipid-laden macrophages (foam cells) within the arterial walls. However, clinical trials that raise HDL cholesterol levels have failed to show a benefit casting doubts on our basic understanding of HDL function. Atherosclerosis is a chronic inflammatory condition underlying CVD and driven in part by the recognition of metabolic danger signals by innate immune receptors on macrophages. A potential feature that could contribute to HDL’s protective effects in CVD could be HDL's anti-inflammatory nature, such as its ability to reduce endothelial cell activation. However, the molecular mechanisms by which HDL reduces inflammatory macrophage responses remain poorly understood and difficult to separate from its cholesterol depleting activity. Here we show that HDL protects against Toll like receptor (TLR)-induced inflammation both in vivo and in vitro under normocholesteremic conditions by suppressing the transcription of inflammatory cytokines in a manner independent of its ability to remove cellular cholesterol. We identify Activating Transcription Factor 3 (ATF3), a transcriptional repressor of the CREB family of basic leucine zipper transcription factors, as a HDL-inducible regulator of macrophage activation. HDL’s ability to down modulate TLR responses was severely compromised in ATF3-deficient cells demonstrating that ATF3 mediates HDL's anti-inflammatory effects and may explain the broad anti-inflammatory functions of HDL.