Abstract
Increasing evidence support that cellular amino acid metabolism shapes the fate of immune cells; however, whether aspartate metabolism dictates macrophage function is still enigmatic. Here, we found that the metabolites in aspartate metabolism are depleted in lipopolysaccharide (LPS) plus interferon gamma (IFN-γ)-stimulated macrophages. Aspartate promotes interleukin-1β (IL-1β) secretion in M1 macrophages. Mechanistically, aspartate boosts the activation of hypoxia-inducible factor-1α (HIF-1α) and inflammasome and increases the levels of metabolites in aspartate metabolism, such as asparagine. Interestingly, asparagine also accelerates the activation of cellular signaling pathways and promotes the production of inflammatory cytokines from macrophages. Moreover, aspartate supplementation augments the macrophage-mediated inflammatory responses in mice and piglets. These results uncover a previously uncharacterized role for aspartate metabolism in directing M1 macrophage polarization.
Highlights
Immune cells are central determinants of the maintenance of physiological homeostasis by protecting the host from environmental stimuli [1]
Aspartate and Its Metabolites Are Depleted in M1 Macrophages
With liquid chromatography– mass spectrometry (LC-MS), our previous study showed a remarkable difference in the cellular metabolism between resting macrophages (M0) and macrophages stimulated with LPS plus interferon gamma (IFN-g) [27]
Summary
Immune cells are central determinants of the maintenance of physiological homeostasis by protecting the host from environmental stimuli [1]. Once immune cells sense pathogeny or other insults, they activate and proliferate rapidly to perform the corresponding immune functions [2]. Multiple contributors are associated with the fate of immune cells. By providing energy and substrates, metabolic pathways and metabolites are vital in modulating immune cell growth and survival and in instructing the effector function of immune cells [2]. Altered amino acid metabolism (e.g., arginine metabolism) is one of characteristics employed to define macrophage polarization [3,4,5,6,7]. Essential amino acids, which cannot be sufficiently synthesized by the body and must obtained from dietary sources, are crucial for the function of immune cells [8]. Methionine is critical for T-cell activation [9], and serine or tryptophan metabolism is associated with macrophage
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