LXRα Regulates oxLDL-Induced Trained Immunity in Macrophages

Reprogramming of metabolic pathways in monocytes and macrophages can induce a proatherosclerotic inflammatory memory called trained innate immunity. Here, we have analyzed the role of the Liver X receptor (LXR), a crucial regulator of metabolism and inflammation, in oxidized low-density lipoprotein (oxLDL)-induced trained innate immunity. Human monocytes were incubated with LXR agonists, antagonists, and oxLDL for 24 h. After five days of resting time, cells were restimulated with the TLR-2 agonist Pam3cys. OxLDL priming induced the expression of <i>LXRα</i> but not <i>LXRβ</i>. Pharmacologic LXR activation was enhanced, while LXR inhibition prevented the oxLDL-induced inflammatory response. Furthermore, LXR inhibition blocked the metabolic changes necessary for epigenetic reprogramming associated with trained immunity. In fact, enrichment of activating histone marks at the <i>IL-6</i> and <i>TNFα</i> promotor was reduced following LXR inhibition. Based on the differential expression of the LXR isoforms, we inhibited <i>LXRα</i> and <i>LXRβ</i> genes using siRNA in THP1 cells. As expected, siRNA-mediated knock-down of <i>LXRα</i> blocked the oxLDL-induced inflammatory response, while knock-down of <i>LXRβ</i> had no effect. We demonstrate a specific and novel role of the LXRα isoform in the regulation of oxLDL-induced trained immunity. Our data reveal important aspects of LXR signaling in innate immunity with relevance to atherosclerosis formation.