The Transcription Factor Nrf2 Is a Therapeutic Target against Brain Inflammation

Abstract

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-α, 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-α) 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.

Role of the Transcription Factor Nrf2 in Parkinson’s Disease: New Insights

“…In the absence of NRF2, NF-κB lacks a controller to switch-off the inflammatory signal [68] (Figure 1). Consistently, in animals treated with SFN, an NRF2 inducer, the production of inflammatory markers in response to LPS was attenuated [63]. These results are sustained by the presence of a NF-κB binding site in the NRF2 coding gene [69] and by the fact that IκK-β (IκBα kinase) contains an ETGE motif that enables it to bind to KEAP1 [70], the repressor protein of NRF2.…”

“…The role of NRF2 in inflammation is supported by the fact that NRF2-deficient mice exhibited exacerbated inflammatory process under different stimuli [39,[63][64][65][66][67]. In the absence of NRF2, NF-κB lacks a controller to switch-off the inflammatory signal [68] (Figure 1).…”

Human CYP2A6 is regulated by nuclear factor-erythroid 2 related factor 2

“…After 18 h, 1 mg/head SFN or saline was intraperitoneally administered. The dose was decided referring previous studies [19,20].…”

NADPH oxidase 2-derived reactive oxygen species in spinal cord microglia contribute to peripheral nerve injury-induced neuropathic pain

“…To address this issue, we directly introduced the antioxidant sulforaphane to WT mice intrathecally. Sulforaphane is known to exert its antioxidant effect by inducing nuclear translocation of Nrf-2 with subsequent heme oxygenase-1 (HO-1) expression in myeloid cells, including the microglia (13). In the spinal cord of SNT-injured mice, sulforaphane injection enhanced the translocation of Nrf2 to the nuclear fraction (Fig.…”