LXRα Regulates oxLDL-Induced Trained Immunity in Macrophages

Abstract

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 LXRα but not LXRβ. 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 TNFα promotor was reduced following LXR inhibition. Based on the differential expression of the LXR isoforms, we inhibited LXRα and LXRβ genes using siRNA in THP1 cells. As expected, siRNA-mediated knock-down of LXRα blocked the oxLDL-induced inflammatory response, while knock-down of LXRβ 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.

Targeting macrophages in atherosclerosis using nanocarriers loaded with liver X receptor agonists: A narrow review

“…Furthermore, LXR activation inhibits the production of a series of pro-inflammatory factors which are stimulated by bacteria, bacterial endotoxin lipopolysaccharide (LPS), TNF-α, and IL-1β. LXR agonists play an important regulatory role in inhibiting the expression of proinflammatory genes in macrophages and other types of cells (Findeisen et al, 2022). LXRα can selectively regulate the expression of genes related to apoptosis and leukocyte migration.…”

Trained immunity as a possible newcomer in autoinflammatory and autoimmune diseases pathophysiology

“…Their increased responsiveness could contribute to the development and/or maintenance of chronic or recurrent inflammation and tissue destruction, which characterize autoinflammatory and autoimmune diseases. The initial stimulus leading to or fueling autoinflammatory and autoimmune diseases remain to be identified, but trained immunity can be induced by endogenous and environmental stimuli, such as oxidized lowdensity lipoprotein (oxLDL) and western diet (115)(116)(117), that are also known or suspected to participate to the development of autoinflammatory and autoimmune diseases (118,119). Consequently, strategies targeting metabolism and epigenetic reprogramming, which represent the hallmarks of trained immunity, are being proposed as potential treatments or prevention strategies of autoinflammation and autoimmunity.…”

Re‐recognition of innate immune memory as an integrated multidimensional concept

“…High levels of fatty acids are sensed as danger signals by PRRs such as the Nod‐like receptor family pyrin domain containing 3 (NLRP3) and toll‐like receptors (TLRs), which stimulate inflammatory responses against further stimuli 71,75 . Accordingly, oxidized low‐density lipoprotein (oxLDL) enhances glycolytic activity and induces innate immune memory in macrophages, thus suggesting the essential role of glycolysis and lipid synthesis pathways in forming the immune memory phenotype 73,76,77 . Apart from these, the involvement of other metabolic pathways (e.g., pentose phosphate pathways and amino acid metabolic pathways) in innate immune memory has also been reviewed in detail 78,79 …”

“…71,75 Accordingly, oxidized low-density lipoprotein (oxLDL) enhances glycolytic activity and induces innate immune memory in macrophages, thus suggesting the essential role of glycolysis and lipid synthesis pathways in forming the immune memory phenotype. 73,76,77 Apart from these, the involvement of other metabolic pathways (e.g., pentose phosphate pathways and amino acid metabolic pathways) innate immune memory has also been reviewed in detail. 78,79 It is still poorly understood how cellular metabolism connects to epigenetic memory in innate immunity, although it is suggested that some products of the TCA cycle (e.g., acetyl-CoA) might be involved in histone modifications during immune memory (Figure 2).…”