Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

LXRα regulates oxLDL-induced trained innate immunity in human macrophages
H. Findeisen1, V. Voges1, L. Braun1, H. Reinecke1, D. Schwarz1, Y. Sohrabi1
1Klinik für Kardiologie I: Koronare Herzkrankheit, Herzinsuffizienz und Angiologie, Universitätsklinikum Münster, Münster;

Objectives:

Reprogramming of cellular metabolic pathways of monocytes and macrophages including cholesterol and fatty acid synthesis can induce a proatherosclerotic inflammatory memory, an emerging new concept called trained innate immunity. Liver X receptor (LXR) is a crucial regulator at the crossroads of metabolism and inflammation and a novel regulator of trained innate immunity. Here, we have analyzed the role of LXR in trained innate immunity induced through stimulation with the proatherogenic factor oxidized low-density lipoprotein (oxLDL).

Methods and Results:

Human monocytes were isolated and incubated with different stimuli for 24h, including LXR agonists, antagonists and oxLDL. After 5 days resting time, cells were restimulated with the TLR2-agonist Pam3cys. OxLDL priming induced the expression of LXRα but not LXRβ. Pharmacologic LXR activation significantly enhanced the oxLDL-induced inflammatory response to TLR2-restimulation. Next, we analyzed the impact of LXR inhibition on the inflammatory, metabolic and epigenetic features of this trained immunity phenotype. LXR inhibition blocked the expression of inflammatory cytokines such as IL-6, TNFα or IL-1. Furthermore, the expression of metabolic enzymes regulating glycolysis as well as lipid synthesis was significantly reduced following LXR inhibition. This was also accompanied by decreased glucose consumption and lactate production. As metabolic reprogramming is a necessary step for the epigenetic implementation of trained immunity, we next analyzed the formation of specific activating histone acetylation and methylation marks on the promoters of IL-6 and TNFα. In line with our previous observation, LXR inhibition blocked the epigenetic changes as well. Based on the differential expression of the LXR isoforms, we also performed RNA-interference experiments. SiRNA-mediated knock down of LXRα blocked the inflammatory response to TLR2-restimulation, while knock down of LXRβ had no effect.

Conclusion: 

We demonstrate a specific and novel role of LXR isoforms in the regulation of monocyte inflammation and identify LXRα as an important regulator of oxLDL-induced proinflammatory trained immunity. Our data reveal important novel aspects of LXR signaling in innate immunity with relevance to atherosclerosis formation.


https://dgk.org/kongress_programme/jt2022/aP1996.html