Abstract
Evidence demonstrates that M1 macrophage polarization promotes inflammatory disease. Here, we discovered that (R)‐salbutamol, a β2 receptor agonist, inhibits and reprograms the cellular metabolism of RAW264.7 macrophages. (R)‐salbutamol significantly inhibited LPS‐induced M1 macrophage polarization and downregulated expressions of typical M1 macrophage cytokines, including monocyte chemotactic protein‐1 (MCP‐1), interleukin‐1β (IL‐1β) and tumour necrosis factor α (TNF‐α). Also, (R)‐salbutamol significantly decreased the production of inducible nitric oxide synthase (iNOS), nitric oxide (NO) and reactive oxygen species (ROS), while increasing the reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio. In contrast, (S)‐salbutamol increased the production of NO and ROS. Bioenergetic profiles showed that (R)‐salbutamol significantly reduced aerobic glycolysis and enhanced mitochondrial respiration. Untargeted metabolomics analysis demonstrated that (R)‐salbutamol modulated metabolic pathways, of which three metabolic pathways, namely, (a) phenylalanine metabolism, (b) the pentose phosphate pathway and (c) glycerophospholipid metabolism were the most noticeably impacted pathways. The effects of (R)‐salbutamol on M1 polarization were inhibited by a specific β2 receptor antagonist, ICI‐118551. These findings demonstrated that (R)‐salbutamol inhibits the M1 phenotype by downregulating aerobic glycolysis and glycerophospholipid metabolism, which may propose (R)‐salbutamol as the major pharmacologically active component of racemic salbutamol for the treatment of inflammatory diseases and highlight the medicinal value of (R)‐salbutamol.
Highlights
Inflammation occurs when immune receptors recognize damaged cells and pathogens
The results showed that treatment with LPS led to a significant nitric oxide (NO) and reactive oxygen species (ROS) elevation in macrophage cells as evidenced by in‐ creased fluorescence intensity, while treatment with various con‐ centrations of (R)‐salbutamol prior to LPS exposure significantly reduced the amount of intracellular NO and ROS induced by LPS in a dose‐dependent manner
We further analysed indices representing an altera‐ tion in mitochondrial respiration and found that basal and maximal respiration was reduced by 71.23% in the LPS‐induced group in contrast to the control group, which indicated some disruption of oxidative phosphorylation (OXPHOS)
Summary
Inflammation occurs when immune receptors recognize damaged cells and pathogens. In‐ flammation is a protective response to internal injury or external pathogens.[1]. An excessive inflammatory response is associ‐ ated with the pathogenesis of many human diseases.[2,3]. As the most abundant innate immune cells, macrophages are critical agents in in‐ flammatory disease. Depending on the type of stimuli, macrophages show phenotypic heterogeneity and have different functional. Recent studies have shown that the relative proportion of macrophage subsets, rather than the absolute number of macro‐ phages, significantly affects disease progression.[4,5]
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