The transcription factor Nrf2 is a therapeutic target against brain inflammation.
Because chronic neuroinflammation is a hallmark of neurodegenerative diseases and compromises neuron viability, it is imperative to discover pharmacologic targets to modulate the activation of immune brain cells, the microglia. In this study, we identify the transcription factor Nrf2, guardian of redox homeostasis, as such target in a model of LPS-induced inflammation in mouse hippocampus. Nrf2 knockout mice were hypersensitive to the neuroinflammation induced by LPS, as determined by an increase in F4/80 mRNA and protein, indicative of an increase in microglial cells, and in the inflammation markers inducible NO synthase, IL-6, and TNF-alpha, compared with the hippocampi of wild-type littermates. The aliphatic isothiocyanate sulforaphane elicited an Nrf2-mediated antioxidant response in the BV2 microglial cell line, determined by flow cytometry of cells incubated with the redox sensitive probe dihydrodichlorofluorescein diacetate, and by the Nrf2-dependent induction of the phase II antioxidant enzyme heme oxygenase-1. Animals treated with sulforaphane displayed a 2-3-fold increase in heme oxygenase-1, a reduced abundance of microglial cells in the hippocampus and an attenuated production of inflammation markers (inducible NO synthase, IL-6, and TNF-alpha) in response to LPS. Considering that release of reactive oxygen species is a property of activated microglia, we propose a model in which late induction of Nrf2 intervenes in the down-regulation of microglia. This study opens the possibility of targeting Nrf2 in brain as a means to modulate neuroinflammation.
Departamento de Bioquímica e Instituto de Investigaciones Biomédicas Alberto Sols Consejo Superior de Investigaciones Científicas-Universidad Autónoma, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
Nadia G
NG
Innamorato
Ana I
AI
Rojo
Angel J
AJ
García-Yagüe
Masayuki
M
Yamamoto
María L
ML
de Ceballos
Antonio
A
Cuadrado
D000818:Animals; D002460:Cell Line; D004660:Encephalitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D017879:Isothiocyanates; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology
D017879:Isothiocyanates; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D013454:Sulfoxides; D013861:Thiocyanates; D051547:Heme Oxygenase-1; C016766:sulforaphane