PTEN regulation of AcetyCoA/HAT activity regulates macrophage activation during Staphylococcus aureus infection.

Abstract

Abstract Sepsis is a life-threatening condition characterized by systemic inflammation, multiple organ failure, and death. Macrophage metabolism and actions play a critical role in sepsis pathogenesis. Fatty acid metabolism was identified as one of the most promising metabolic predictors for survival in sepsis. The phosphatase and tensin homolog (PTEN) is a critical regulator of cell growth and metabolism and influences different arms of the innate immune response. Here, we seek to investigate whether PTEN is a bridge between immunometabolism and gene expression in macrophages during S. aureus infection, WT (PTEN fl/fl) and KO (PTEN fl/fl_LysM Cre) were infected i.v. with methicillin-resistant Staphylococcus aureus (MRSA) and kidney and blood were collected on day three. PTEN deficiency decreased MRSA kidney bacterial loads, as evidenced by IVIS. Bulk RNAseq analysis of kidney macrophages from infected WT and PTEN KO mice showed reduced expression of genes involved in fat acids synthesis, such as (FASN), which correlated with decreased levels of cellular acetyl-coenzyme A in MRSA-infected macrophages. Acetyl-CoA is a substrate for the epigenetic enzyme histone acetyltransferase (HAT) and favors gene expression. Infected PTEN KO macrophages showed lower nuclear p300/CBP HAT activity than cells from WT mice and decreased H3K9 and H3K18 acetylation (involved in open chromatin) in infected macrophages. Studies underpinning the role of the PTEN/HAT axis in MRSA infection are underway. These data suggest that PTEN is required for gene expression of genes involved in fatty acid metabolism, which might reduce the cytokine storm seen during sepsis.