Macrophages have crucial roles in the immune system and respond to environmental cues which regulate their function. Generally, these have been categorised as either a pro-inflammatory or anti-inflammatory phenotype. Recently, these functional phenotypes have been associated with changes in metabolism, where pro-inflammatory macrophages have high glycolytic rates and anti-inflammatory macrophages predominantly use oxidative phosphorylation. Activation of the sympathetic nervous system releases catecholamines which are involved in cross-talk between the neuro-endocrine and immune system. There is evidence to suggest that β-adrenergic (βAR) signalling has an anti-inflammatory effect on the immune system. However, the effect of β-adrenergic signalling on macrophage metabolism is unknown. To address this, an untargeted metabolomics approach was used to explore the effects of β-agonism on the metabolome of lipopolysaccharide (LPS)-treated macrophages.
LPS stimulation of murine bone marrow-derived macrophages increased the levels of metabolites in glycolysis, pentose phosphate pathway and nucleotide metabolism, which is consistent with prior literature. Addition of the βAR agonist, isoprenaline, decreased the levels of these metabolites by 20-50% compared to LPS-treated macrophages. Extracellular flux analysis confirmed an isoprenaline-induced reduction in glycolytic rate at early and late phase LPS activation. 13C-glucose labelling supported the finding of LPS-induced flux of glucose into the pentose phosphate pathway, and the addition of isoprenaline to LPS-treated macrophages resulted in reduced levels of metabolites in the non-oxidative branch of the pentose phosphate pathway. The 13C-glucose labelling also suggests reduced de novo biosynthesis of purines and pyrimidines. However, total pools of nucleotides were abundant in both LPS-treated groups (+/- isoprenaline), suggesting active salvage pathways. In functional studies, isoprenaline was found to reduce LPS-mediated production of pro-inflammatory cytokines by 20-50%. Further studies are evaluating the molecular mechanisms causing β-adrenergic mediated suppression of metabolism in LPS-stimulated macrophages, and the effect altered metabolism has on function.