Pathogens Take a Toll on Lipid Metabolism

Science's STKE  28 Oct 2003:
Vol. 2003, Issue 206, pp. tw418
DOI: 10.1126/stke.2003.206.tw418

Castrillo et al. demonstrated cross talk between Toll-like receptors (TLRs, which are used to recognize pathogen-associated motifs) and LXRs (liver X receptors, transcriptional regulators of cholesterol metabolism that are critical to the homeostatic response of macrophages to lipid loading), providing a mechanism whereby pathogens may contribute to cardiovascular disease. Viral and bacterial infections have long been suspected of contributing to the pathogenesis of atherosclerosis--which involves chronic inflammation as well as disordered lipid metabolism--but the mechanisms whereby innate immune responses might interact with lipid metabolism have been unclear. Castrillo et al. infected cultured murine macrophages with Escherichia coli or the influenza A virus and used Northern analysis or real-time quantitative polymerase chain reaction to show that these infections inhibited the ability of LXR agonists to induce the expression of genes involved in cholesterol efflux and lipid metabolism. TLR3 and TLR4 ligands inhibited the expression of LXR-target genes (including apoE and the cholesterol transporter ABCA1), as well as the efflux of cholesterol from macrophages. The authors used cells transfected with gene reporters to show that application of TLR3 and TLR4 ligands interfered with the ability of LXR to transcriptionally activate its targets. Experiments in various gain-of-function and loss-of-function systems indicated that these effects of TLR signaling were independent of the canonical TLR pathway that involves myeloid differentiation factor 88, nuclear factor-κB activation, and interferon production, and were mediated by the transcription factor IRF3. Thus, TLR signaling, by inhibiting LXR-dependent pathways, may provide a mechanism whereby pathogens can interfere with macrophage handling of cholesterol and thereby promote atherosclerosis.

A. Castrillo, S. B. Joseph, S. A. Vaidya, M. Haberland, A. M. Fogelman, G. Cheng, P. Tontonoz, Crosstalk between LXR and Toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism. Mol. Cell 12, 805-816 (2003). [Online Journal]