High levels of high-density lipoprotein (HDL) in the blood are associated with protection from cardiovascular disease. How HDL also exerts anti-inflammatory properties is now shown in mouse models of acute inflammation—HDL induces expression of ATF3 in macrophages and reduces cytokine production (Nat. Immunol. 15, 152–160, 2014).

Eicke Latz and his colleagues show in a model of acute inflammation that pretreatment of mice with human HDL reduces proinflammatory cytokine production and liver injury after exposure to Toll-like receptor (TLR) agonists. These effects seem to be mediated at the transcriptional level, as HDL reduced mRNA expression of cytokines in macrophages incubated with TLR agonists without impairing cytokine secretion. Through microarray analyses, the authors pinpointed the transcriptional regulator ATF3 as the major HDL target in macrophages in culture, whose expression was strongly upregulated in the presence of HDL. The lack of ATF3 in macrophages impaired the anti-inflammatory effects of HDL in vitro, and HDL did not protect Atf3-deficient mice from TLR-induced inflammation in vivo. Moreover, HDL normally promotes reendothelialization after carotid artery injury; this effect of HDL was also impaired in mice lacking ATF3.

Given the broad role of HDL as modulator of TLR responses in macrophages, its effects may be beneficial not only in the context of atherosclerosis and cardiovascular disease but also in other inflammatory diseases.