Histone deacetylase (HDAC) inhibitors reduce the glial inflammatory response in vitro and in vivo.
Histone deacetylase inhibitors (HDACi) are emerging tools for epigenetic modulation of gene expression and suppress the inflammatory response in models of systemic immune activation. Yet, their effects within the brain are still controversial. Also, whether HDACs are expressed in astrocytes or microglia is unclear. Here, we report the identification of transcripts for HDAC 1-11 in cultured mouse glial cells. Two HDACi such as SAHA and ITF2357 induce dramatic increase of histone acetylation without causing cytotoxicity of cultured cells. Of note, the two compounds inhibit expression of pro-inflammatory mediators by LPS-challenged glial cultures, and potentiate immunosuppression triggered by dexamethasone in vitro. The anti-inflammatory effect is not due to HDACi-induced transcription of immunosuppressant proteins, (including SOCS-1/3) or microRNA-146. Rather, it is accompanied by direct alteration of transcription factor DNA binding and ensuing transcriptional activation. Indeed, both HDACi impair NFkappaB-dependent IkappaBalpha resynthesis in glial cells exposed to LPS, and, among various AP1 subunits and NFkappaB p65, affect the DNA binding activity of c-FOS, c-JUN and FRA2. Importantly, ITF2357 reduces the expression of pro-inflammatory mediators in the striatum of mice iontophoretically injected with LPS. Data demonstrate that mouse glial cells have ongoing HDAC activity, and its inhibition suppresses the neuroinflammatory response because of a direct impairment of the transcriptional machinery.
Faraco
Giuseppe
G
Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy.
Pittelli
Maria
M
Cavone
Leonardo
L
Fossati
Silvia
S
Porcu
Marco
M
Mascagni
Paolo
P
Fossati
Gianluca
G
Moroni
Flavio
F
Chiarugi
Alberto
A
D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000187:drug effects / Q000201:enzymology*
D056572:Histone Deacetylase Inhibitors; D018836:Inflammation Mediators; D006655:Histone Deacetylases