Macrophage liver X receptors (LXRs) are members of the nuclear receptor superfamily of transcription factors and are bound and activated by naturally occurring oxysterols. LXRs are central regulators of lipid homeostasis and inflammation, and play an important role to inhibit atherosclerosis in animal models. Recent studies suggest that a SUMOylation-dependent pathway regulates LXR anti-inflammatory function. Our preliminary data suggests that although Toll-like-receptor (TLR) 4 and interferon induced gene activation can be repressed by LXRs and PPAR agonists, LXR transrepression is selectively abolished when we stimulate the cells with TLR2 ligands. This argues for a signal and nuclear receptor specific mechanism in over-ridding the SUMOylation-dependent anti-inflammatory function of LXRs.
The aim of this proposal is to investigate the molecular mechanisms by which TLR2 negatively regulates the anti-inflammatory function of LXR.
Three specific aims are proposed for this investigation. First, I will determine whether TLR2 blocks LXR function by inducing direct interaction and phosphorylation of LXR by CaMKII using biochemical assays.
The second aim i s to test the hypothesis that CaMKII-mediated phosphorylation leads to deSUMOylation of LXR, which may alter the affinity of LXR for NCoR complex and its ability to transrepress in siRNA knockdown studies.
The third aim i s to test the hypothesis that TLR2 activated CaMKII blocks LXR function at a genome-wide level using microarray and ChlP-Sequencing technologies. Macrophage-mediated inflammatory responses are important contributors to many chronic inflammatory diseases, including atherosclerosis and diabetes. Understanding of the molecular mechanisms of regulation of LXR function could provide important information for designing therapeutic approaches for treating atherosclerosis and other chronic inflammatory diseases.
| Huang, Wendy; Ghisletti, Serena; Saijo, Kaoru et al. (2011) Coronin 2A mediates actin-dependent de-repression of inflammatory response genes. Nature 470:414-8 |
| Huang, Wendy; Glass, Christopher K (2010) Nuclear receptors and inflammation control: molecular mechanisms and pathophysiological relevance. Arterioscler Thromb Vasc Biol 30:1542-9 |
