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

ABSTRACT: Macrophages are key immune cells in tissues that are able to adapt their metabolic phenotype in response to different stimuli. Lysine deacetylases are important enzymes for regulating inflammatory gene expression and their inhibitors have anti-inflammatory effects in models of chronic obstructive pulmonary disease (COPD). We hypothesized that these anti-inflammatory effects may be driven by or associated with metabolic changes in macrophages. To validate this hypothesis, we used an unbiased and a targeted proteomic approach to investigate metabolic enzymes and LC- and GC-MS to quantify metabolites in combination with functional parameters in primary murine alveolar-like macrophages after lipopolysaccharide (LPS)-induced activation with and without lysine deacetylase inhibitors. We found that lysine deacetylase inhibitor treatment resulted in reduced production of inflammatory mediators such as TNF-α and IL-1β. However, only minor changes in macrophage metabolism were observed, as only one of the deacetylase inhibitors slightly increased mitochondrial respiration. However, lysine deacetylase inhibition specifically enhanced expression of proteins involved in ubiquitination, and this may be a potential driver of the anti-inflammatory effects of lysine deacetylase inhibitors. Our data illustrate that a multi-omics approach is necessary to gain a better understanding of how macrophages interact with cues from their environment. More detailed insight into the molecular mechanisms of KDAC inhibition is needed and investigating ubiquitination seems a promising next step. This is important as conventional anti-inflammatory drugs like corticosteroids have low effectiveness in many patients and novel therapeutic strategies are urgently needed.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Macrophage

SUBMITTER: Justina Clarinda Wolters  

LAB HEAD: Justina Clarinda

PROVIDER: PXD040933 | Pride | 2024-02-21

REPOSITORIES: Pride