High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3

Abstract

High Density Lipoprotein (HDL) mediates reverse cholesterol transport and it is known to be protective against atherosclerosis. In addition, HDL has potent anti-inflammatory properties that may be critical for protection against other inflammatory diseases. The molecular mechanisms of how HDL can modulate inflammation, particularly in immune cells such as macrophages, remain poorly understood. Here we identify the transcriptional repressor ATF3, as an HDL-inducible target gene in macrophages that down-regulates the expression of Toll-like receptor (TLR)-induced pro-inflammatory cytokines. The protective effects of HDL against TLR-induced inflammation were fully dependent on ATF3 in vitro and in vivo. Our findings may explain the broad anti-inflammatory and metabolic actions of HDL and provide the basis for predicting the success of novel HDL-based therapies.

Complement Factor H Binds to Human Serum Apolipoprotein E and Mediates Complement Regulation on High Density Lipoprotein Particles

“…B, for microscale thermophoresis analysis FH5-7 was incubated with labeled apoE2. The concentration of labeled ligand was 0.0013 M, and the starting concentration for the unlabeled FH5-7 was 5 M. The average of two experiments suggested a K d value of 0.202 M. vitro and in vivo studies, it is evident that HDL has an important role in reducing inflammation (28). This is possibly at least partially due to binding of complement regulators FH and clusterin to HDL particles.…”

Glucocorticoid Induces Hepatic Steatosis by Inhibiting Activating Transcription Factor 3 (ATF3)/S100A9 Protein Signaling in Granulocytic Myeloid-derived Suppressor Cells

“…ATF3 functions as a negative regulator of the inflammatory responses in macrophages by antagonizing TLR-induced NF-B signaling (35), and ATF3 deletion increases lipid accumulation and foam cell formation through epigenetic repression of the cholesterol 25-hydroxylase gene Ch25h (36). ATF3 has been demonstrated to mediate the anti-inflammatory and metabolic activities of high density lipoprotein (HDL) by down-regulating TLR-induced proinflammatory cytokines (37). Here, we provide novel evidence that ATF3 plays an important role in linking lipid metabolism and immunity through regulation of MDSC development and activation.…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…Thus, Atf3 −/− mice are more susceptible to endotoxic shock due to excessive cytokine production (Hoetzenecker et al 2012). ATF3 also mediates high-density lipoprotein (HDL)-induced anti-inflammatory reprogramming of macrophages by transcriptional repression of inflammatory genes (De Nardo et al 2014). In neutrophils, ATF3 restricts neutrophil recruitment by reducing neutrophil chemokine production that promotes neutrophil chemotaxis (Boespflug et al 2014).…”