Inhibitory effect of short-chain fatty acids on the induction of nitric oxide by Staphylococcus aureus lipoproteins in macrophages

Abstract

Abstract Staphylococcus aureus is a Gram-positive bacterial pathogen that can cause severe inflammation often resulting in life-threatening diseases. Lipoproteins of S. aureus are a major virulence factor to induce excessive inflammatory mediators such as nitric oxide (NO) in macrophages. Short-chain fatty acids (SCFAs) such as butyrate, propionate, and acetate are commensal bacteria-derived metabolites in the gut that are known to have anti-inflammatory effects. In this study, we investigated the effects of SCFAs on S. aureus lipoprotein (Sa.LPP)-induced NO production in mouse macrophages. Butyrate and propionate, but not acetate, inhibited Sa.LPP-induced production of NO in RAW 264.7 cells and mouse bone marrow-derived macrophages. Butyrate and propionate inhibited Sa.LPP-induced expression of inducible NO synthase (iNOS). However, acetate did not show such effect under the same conditions. Furthermore, butyrate and propionate, but not acetate, inhibited Sa.LPPinduced activation of NF-κB, expression of IFN-β, and phosphorylation of STAT1, which are essential for inducing transcription of iNOS in macrophages. In addition, butyrate and propionate induced histone acetylation at lysine residues in the presence of Sa.LPP in RAW 264.7 cells. Moreover, Sa.LPP-induced NO production was decreased by histone deacetylase (HDAC) inhibitors. Collectively, these results suggest that the SCFAs butyrate and propionate attenuate the inflammatory responses caused by S. aureus lipoproteins through the inhibition of NF-κB, IFN-β/STAT1, and HDAC, resulting in attenuated NO production in macrophages.