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Abstract
ObjectivesThe concept of trained innate immunity describes a long-term proinflammatory memory in innate immune cells. Trained innate immunity is regulated through reprogramming of cellular metabolic pathways including cholesterol and fatty acid synthesis. Here, we have analyzed the role of Liver X Receptor (LXR), a key regulator of cholesterol and fatty acid homeostasis, in trained innate immunity.Methods and ResultsHuman monocytes were isolated and incubated with different stimuli for 24 h, including LXR agonists, antagonists and Bacillus Calmette-Guerin (BCG) vaccine. After 5 days resting time, cells were restimulated with the TLR2-agonist Pam3cys. LXR activation did not only increase BCG trained immunity, but also induced a long-term inflammatory activation by itself. This inflammatory activation by LXR agonists was accompanied by characteristic features of trained innate immunity, such as activating histone marks on inflammatory gene promoters and metabolic reprogramming with increased lactate production and decreased oxygen consumption rate. Mechanistically, LXR priming increased cellular acetyl-CoA levels and was dependent on the activation of the mevalonate pathway and IL-1β signaling. In contrast to mevalonate pathway inhibition, blocking fatty acid synthesis further increased proinflammatory priming by LXR.ConclusionWe demonstrate that LXR activation induces a proinflammatory trained immunity phenotype in human monocytes through epigenetic and metabolic reprogramming. Our data reveal important novel aspects of LXR signaling in innate immunity.
Highlights
Innate immune cells such as monocytes and macrophages retain a high phenotypic plasticity in response to environmental cues to be able to rapidly fulfill their diverse functions in host defense and tissue homeostasis [1]
Considering the extensive evidence demonstrating regulatory functions of Liver X receptors (LXRs) in innate immunity and lipid metabolism, we have studied the effect of LXR activation in monocyte trained innate immunity
Cholesterol and fatty acid metabolism have been implicated in the regulation of trained innate immunity [10, 14]
Summary
Innate immune cells such as monocytes and macrophages retain a high phenotypic plasticity in response to environmental cues to be able to rapidly fulfill their diverse functions in host defense and tissue homeostasis [1]. The term immunometabolism has been introduced to describe this regulation of immune cell function through intracellular metabolic pathways. Netea et al have introduced the concept of trained innate immunity or innate immune memory to describe a long-term adaption of innate immune cells to respond to certain stimuli with an enhanced inflammatory response [4]. Immunometabolic reprogramming of various pathways including glycolysis, oxidative phosphorylation, glutaminolysis as well as fatty acid and cholesterol metabolism controls trained innate immunity [5]. Recent evidence has highlighted the crucial role of cholesterol and fatty acid synthesis in regulating trained innate immunity [10, 13]. Fatty acid metabolites are involved in the regulation of trained-immunity-associated effects on hematopoietic progenitors in vivo [14]
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