LXRα Regulates oxLDL-Induced Trained Immunity in Macrophages
Hannes M. Findeisen; Vivienne C. Voges; Laura C. Braun; Jannik Sonnenberg; Dennis Schwarz; Helena Körner; Holger Reinecke; Yahya Sohrabi
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.
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