Histone deacetylase inhibitors impair innate immune responses to Toll-like receptor agonists and to infection.
Regulated by histone acetyltransferases and deacetylases (HDACs), histone acetylation is a key epigenetic mechanism controlling chromatin structure, DNA accessibility, and gene expression. HDAC inhibitors induce growth arrest, differentiation, and apoptosis of tumor cells and are used as anticancer agents. Here we describe the effects of HDAC inhibitors on microbial sensing by macrophages and dendritic cells in vitro and host defenses against infection in vivo. HDAC inhibitors down-regulated the expression of numerous host defense genes, including pattern recognition receptors, kinases, transcription regulators, cytokines, chemokines, growth factors, and costimulatory molecules as assessed by genome-wide microarray analyses or innate immune responses of macrophages and dendritic cells stimulated with Toll-like receptor agonists. HDAC inhibitors induced the expression of Mi-2β and enhanced the DNA-binding activity of the Mi-2/NuRD complex that acts as a transcriptional repressor of macrophage cytokine production. In vivo, HDAC inhibitors increased the susceptibility to bacterial and fungal infections but conferred protection against toxic and septic shock. Thus, these data identify an essential role for HDAC inhibitors in the regulation of the expression of innate immune genes and host defenses against microbial pathogens.
Infectious Diseases Service, Department of Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, rue du Bugnon 46, Lausanne, Switzerland. Thierry.Roger@chuv.ch
Thierry
T
Roger
Jérôme
J
Lugrin
Didier
D
Le Roy
Geneviève
G
Goy
Matteo
M
Mombelli
Thibaud
T
Koessler
Xavier C
XC
Ding
Anne-Laure
AL
Chanson
Marlies Knaup
MK
Reymond
Isabelle
I
Miconnet
Jacques
J
Schrenzel
Patrice
P
François
Thierry
T
Calandra
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects* / Q000235:genetics; D007239:Infections / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D046228:Microarray Analysis; D051193:Toll-Like Receptors / Q000819:agonists*
D056572:Histone Deacetylase Inhibitors; D051193:Toll-Like Receptors