High-density lipoprotein (HDL), or “good cholesterol,” is well known for its protective effects, which include not only the slowing of atherosclerosis, but also the prevention of inflammation. Merely increasing HDL levels, however, does not reduce the incidence of atherosclerosis. And even though HDL is known to lessen the inflammatory zeal of immune cells, the details of this moderating effect have been poorly understood.
In hopes of clarifying the molecular mechanisms behind HDL’s protective effects, an international team of scientists working at the University of Bonn in Germany identified a large number of genes that appeared to be regulated by high HDL levels. This work, which took about three years, involved extensive experiments in human and mouse cells. Then, with the aid of genomic and bioinformatics approaches, the scientists sifted through the wealth of candidate genes until they finally filtered out ATF3, a transcriptional regulator of gene expression.
This work was summarized in an article published December 8 in Nature Immunology, in an article entitled “High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3.” In this article, the authors noted that ATF3 “downregulates the expression of Toll-like receptor-induced proinflammatory cytokines.”
ATF3 is found in phagocytes, which form part of the innate immune defense system. Phagocytes, with the help of the so-called Toll-like receptors (TLR), can recognize dangerous intruders and initiate an inflammatory response.
The TLR trigger the release of inflammatory substances via biochemical signaling pathways. The ATF3 gene plays a key role in this process. “It reduces the transcription of the inflammatory genes and prevents further stimulation of inflammatory processes via the Toll-like receptors,” reported Dominic De Nardo, Ph.D., an Australian researcher training in the lab of Professor Eicke Latz, director of the Institute of Innate Immunity at the University of Bonn.
The immune system uses inflammatory processes to keep pathogens in check, to detect damaged tissue, and then repair it. In sustained inflammatory reactions, however, there are dangerous consequences including blood poisoning or organ failure. “The transcriptional regulator ATF3 acts to reduce these inflammatory reactions by suppressing the activation of inflammatory genes following excessive stimulation of immunoreceptors,” explained Dr. De Nardo.
In their paper, the scientists indicated that 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,” they added.
In the end, HDL is responsible for downregulating the inflammatory reactions, via the activation of ATF3. “To put it simply, high HDL levels in blood are an important protective factor against sustained inflammation,” summarized Professor Latz. “Our studies also indicate that the amount of HDL in blood alone is not decisive for the protective function of HDL, but that the anti-inflammatory function is probably more important. These results also suggest a molecular approach for treating inflammation in other widespread diseases, such as diabetes.”