Anti-Inflammatory Effects of High-Density Lipoprotein Through Activating Transcription Factor 3

High-density lipoprotein (HDL) cholesterol levels are inversely proportional to the risk of atherosclerosis. However, the evidence that raising HDL per se will reduce atherosclerosis and thereby cardiovascular events remains controversial, and mechanisms of putative HDL-mediated atheroprotection remain unclear. In addition to canonical role of HDL in mobilizing excess cholesterol from arterial wall macrophages (the first step in reverse cholesterol transport), there is compelling evidence to support the anti-inflammatory effects of HDL, both dependent and independent of its cholesterol transport capacities.1Macrophages serve as important orchestrators of inflammation at the intersection of immunity, metabolism, and cardiovascular diseases. Yet anti-inflammatory effects of HDL in macrophages are less well understood. In a recent issue of Nature Immunology , De Nardo et al2 report that anti-inflammatory effects of HDL in macrophages are mediated through the induction of activating transcription factor 3 (ATF3), an ancient transcriptional modulator that provides negative feedback on toll-like receptor (TLR) innate immune signaling.The authors first describe that pretreatment with both native HDL and reconstituted HDL (apoA-I and phospholipids) inhibited cytokine production by multiple distinct TLR ligands in murine bone marrow–derived macrophages (BMDM), human peripheral blood mononuclear cells, and TLR ligand–treated mice, an in vivo model of acute inflammation and liver injury. Although HDL is known to interact and neutralize the TLR4 ligand lipopolysaccharide directly, the authors showed that HDL did not interact with TLR1/2 ligands (Pam3CSK4) and the TLR9 ligand (CpG DNA) and did not directly modulate TLR1/2/9 activation, signaling transduction (eg, …