Histone Deacetylase Inhibitors Impair Antibacterial Defenses of Macrophages

J Infect Dis. 2011 Nov;204(9):1367-74. doi: 10.1093/infdis/jir553. Epub 2011 Sep 15.

Abstract

Histone deacetylases (HDACs) control gene expression by deacetylating histones and nonhistone proteins. HDAC inhibitors (HDACi) are powerful anticancer drugs that exert anti-inflammatory and immunomodulatory activities. We recently reported a proof-of-concept study demonstrating that HDACi increase susceptibility to bacterial infections in vivo. Yet, still little is known about the effects of HDACi on antimicrobial innate immune defenses. Here we show that HDACi belonging to different chemical classes inhibit at multiple levels the response of macrophages to bacterial infection. HDACi reduce the phagocytosis and the killing of Escherichia coli and Staphylococcus aureus by macrophages. In line with these findings, HDACi decrease the expression of phagocytic receptors and inhibit bacteria-induced production of reactive oxygen and nitrogen species by macrophages. Consistently, HDACi impair the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits and inducible nitric oxide synthase. These data indicate that HDACi have a strong impact on critical antimicrobial defense mechanisms in macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Escherichia coli / immunology*
  • Female
  • Histone Deacetylase Inhibitors / pharmacology*
  • Immunologic Factors / physiology*
  • Macrophages / drug effects
  • Macrophages / immunology*
  • Macrophages / microbiology*
  • Mice
  • Mice, Inbred BALB C
  • Microbial Viability
  • NADPH Oxidases / antagonists & inhibitors
  • Nitric Oxide Synthase Type II / antagonists & inhibitors
  • Phagocytosis / drug effects
  • Phagocytosis / immunology
  • Reactive Nitrogen Species / metabolism
  • Reactive Oxygen Species / metabolism
  • Staphylococcus aureus / immunology*

Substances

  • Histone Deacetylase Inhibitors
  • Immunologic Factors
  • Reactive Nitrogen Species
  • Reactive Oxygen Species
  • Nitric Oxide Synthase Type II
  • NADPH Oxidases