LXR alpha 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 LXR alpha but not LXR beta. 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 IL-6 and TNF alpha promotor was reduced following LXR inhibition. Based on the differential expression of the LXR isoforms, we inhibited LXR alpha and LXR beta genes using siRNA in THP1 cells. As expected, siRNA-mediated knock-down of LXR alpha blocked the oxLDL-induced inflammatory response, while knock-down of LXR beta had no effect. We demonstrate a specific and novel role of the LXR alpha 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.