Lipid metabolism as a mechanism of immunomodulation in macrophages: the role of liver X receptors
Introduction
The Liver X Receptors, LXRs, are crucial transcription factors in macrophages that act as important mediators in cholesterol metabolism and modulate several anti-inflammatory pathways [1]. There are two isoforms of LXRs, LXRα, encoded by the gene Nr1h3, and LXRβ, encoded by the gene Nr1h2, with highly similar sequence but diverse tissue distribution. While LXRα shows a higher expression in adipose tissue, liver and macrophages, LXRβ expression is equally found in all tissues and cell types analyzed. Their transcriptional regulation depends on activation by their endogenous ligands, such as oxidized forms of cholesterol, desmosterol and elevated concentrations of d-glucose, as well as synthetic ligands that provide promising therapeutic approaches [2]. Numerous studies investigating Lxrα−/−, Lxrβ−/−, or Lxrα/β−/− mice show mostly overlapping, but also some specific functions of both isoforms of LXR. For example, mice deficient in LXRα lose their natural resistance to a diet rich in cholesterol, showing an accumulation of hepatic cholesterol and a substantially altered conversion of cholesterol into bile acid [3]. Moreover, LXRα is specifically implicated in the developmental pathways that lead to the establishment of tissue-resident macrophages both in the liver and in the spleen [4,5•]. It has been long demonstrated that LXRs play a central role in the anti-inflammatory response in macrophages and that a deficient regulation of their activity can lead to chronic inflammatory conditions [6]. Consequently, targeting LXR nuclear receptors activity in macrophages has a great immunomodulatory potential in metabolic and inflammatory disease. An important challenge to overcome in the therapeutic approaching to target LXRs is the connection between metabolism and immune regulation. Hence, it is crucial to understand LXR transcriptional activity as a central regulator of immunometabolic pathways that determine macrophage immunomodulation. Although evident links between lipid metabolism and immunity are regulated through LXR transcriptional activity, the specific mechanisms of this regulation in vivo have remained difficult to decipher. In this review, we address the central role of the LXR nuclear receptors as regulators of macrophage immune plasticity during metabolic and inflammatory diseases, as well as during development. Moreover, this review gives an overview on the diverse mechanisms by which LXR-dependent lipid metabolic pathways interconnect with immune functions in macrophages, defining novel mechanisms of immunomodulation.
Section snippets
Pleiotropic effects of liver X receptors in lipid-related pathways in macrophages
The first evidences of the role of LXRs in lipid metabolism were provided by the group of David Mangelsdorf in 1998, when they described the regulation of the gene CYP7A1 (an enzyme responsible for bile acid synthesis) by LXRα in mice [3,7]. This study showed that high cellular cholesterol levels are necessary to induce the upregulation of CYP7A1 expression via LXRα, supporting that the endogenous ligands of LXRα are derivate forms of cholesterol, as it was previously shown in vitro [8]. Over
Anti-inflammatory response via LXR-transcriptional regulation
Several studies have explored the role of LXRs in macrophage inflammatory pathways, showing a reciprocal relationship between lipid metabolism and inflammatory gene expression in macrophages [35,36•,37]. The first studies on LXRs and inflammation showed that the activation of LXR by their ligands inhibit the expression of inflammatory mediators (iNOS, Il-6) in macrophages in response to bacterial infection or LPS stimulation in vitro [38]. In vivo, LXR agonists reduce inflammation in
Roles of LXR in macrophage development and differentiation
Over the last decade, our view of tissue-resident macrophage development has evolved from the general dogma that all tissue macrophages develop through differentiation from monocyte precursors [56,57]. Several tissue-resident macrophage populations, such as microglia in the central nervous system and Langerhans cells in the skin, are established embryonically and derived from yolk sac progenitors that self-maintain in the adult through proliferation [58]. Furthermore, the capacity to
Conclusions and future perspectives
Macrophages have the great ability to adopt different phenotypes and functions in response to environmental stimuli. This immune plasticity is modulated through the regulation of numerous signaling pathways and metabolic routes. The LXR nuclear receptors have arisen as key modulators of the immune phenotype and functions in macrophages using several mechanisms in health and disease. For many years the dual role of LXRs in macrophages regulating cholesterol metabolism and modulating the
Conflict of interest statement
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All authors have participated in (a) conception and design, or analysis and interpretation of the data; (b) drafting the article or revising it critically for important intellectual content; and (c) approval of the final version.
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This manuscript has not been submitted to, nor is under review at, another journal or other publishing venue.
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The authors have no affiliation with any organization with a direct or indirect financial interest in the subject matter discussed in the manuscript.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
CRediT authorship contribution statement
Sophia Leussink: Writing - original draft. Irene Aranda-Pardos: Writing - original draft. Noelia A-Gonzalez: Writing - original draft, Supervision.
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These authors contributed equally.