Effects of lysine deacetylase inhibitor treatment on LPS responses of alveolar-like macrophages.

Abstract

Macrophages are key immune cells that can adapt their metabolic phenotype in response to different stimuli. Lysine deacetylases are important enzymes regulating inflammatory gene expression and lysine deacetylase inhibitors have been shown to exert anti-inflammatory effects in models of chronic obstructive pulmonary disease. We hypothesized that these anti-inflammatory effects may be associated with metabolic changes in macrophages. To validate this hypothesis, we used an unbiased and a targeted proteomic approach to investigate metabolic enzymes, as well as liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry, to quantify metabolites in combination with the measurement of functional parameters in primary murine alveolar-like macrophages after lipopolysaccharide-induced activation in the presence or absence of lysine deacetylase inhibition. We found that lysine deacetylase inhibition resulted in reduced production of inflammatory mediators such as tumor necrosis factor α and interleukin 1β. However, only minor changes in macrophage metabolism were observed, as only one of the lysine deacetylase inhibitors slightly increased mitochondrial respiration while no changes in metabolite levels were seen. However, lysine deacetylase inhibition specifically enhanced expression of proteins involved in ubiquitination, which may be a driver of the anti-inflammatory effects of lysine deacetylase inhibitors. Our data illustrate that a multiomics approach provides novel insights into how macrophages interact with cues from their environment. More detailed studies investigating ubiquitination as a potential driver of lysine deacetylase inhibition will help developing novel anti-inflammatory drugs for difficult-to-treat diseases such as chronic obstructive pulmonary disease.