Macrophages have a key role in atherosclerosis through two processes: first, the production of inflammatory mediators; and second, the accumulation of oxidized lipids, as a result of which they become 'foam cells' — macrophages that have taken up massive amounts of lipids, which are the main component of early atherosclerotic lesions. The activation of a class of nuclear-hormone transcription factors known as liver X receptors (LXRs) by oxidized lipids induces the expression of genes involved in lipid efflux in macrophages, thereby acting to protect them from lipid overload. Indeed, recent studies have shown that activating LXR with synthetic agonists can reduce atherosclerosis in mice. Now, Peter Tontonoz, David Mangelsdorf and colleagues have shown that the atheroprotective effect of LXR agonists could be due to a reduction in the the production of inflammatory mediators by macrophages as well as to their established effects on lipid metabolism.

First, the authors assessed the effects of LXR activation on the expression of genes involved in the innate immune response. Macrophages from wild-type mice and from mice lacking LXRs were treated with an LXR agonist, before inducing an immune response by adding bacterial lipopolysaccharide. A comparison of gene expression between cells with and without LXRs using DNA microarrays showed that in cells with LXR present the genes most highly induced by the LXR agonist were those involved in lipid metabolism, as expected from previous understanding. But in addition, the expression of several genes involved in the macrophage innate immune response — such as those encoding inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6) and matrix metalloproteinase 9 (MMP-9) — were inhibited by the LXR agonist. Therefore, in activated macrophages, the cholesterol-efflux pathway and the innate immune response are reciprocally regulated by LXRs.

What influence could such effects have in atherosclerosis, in which inflammatory mediators such as IL-6 and MMP-9 are important? To investigate this, the authors analysed gene expression in the aortas of atherosclerotic mice, and found that treatment with an LXR agonist substantially reduced the expression of MMP-9 (although iNOS expression levels did not differ significantly, indicating that some genes are more sensitive than others to loss of LXR signalling). So, it seems that LXR agonists might reduce atherosclerosis not only by promoting cholesterol efflux, but also by acting to limit the production of inflammatory mediators in the artery wall. Furthermore, LXR agonists might also have potential for other chronic inflammatory diseases in which activated macrophages have a key role, such as rheumatoid arthritis.