Abstract
Sulforaphane (SFN) is a natural product with cytoprotective, anti-inflammatory, and antioxidant effects. In this study, we evaluated the mechanisms of its effects on lipopolysaccharide (LPS)-induced cell death, inflammation, oxidative stress, and polarization in murine microglia. We found that SFN protects N9 microglial cells upon LPS-induced cell death and suppresses LPS-induced levels of secreted pro-inflammatory cytokines, tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6. SFN is also a potent inducer of redox sensitive transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), which is responsible for the transcription of antioxidant, cytoprotective, and anti-inflammatory genes. SFN induced translocation of Nrf2 to the nucleus via extracellular signal-regulated kinase 1/2 (ERK1/2) pathway activation. siRNA-mediated knockdown study showed that the effects of SFN on LPS-induced reactive oxygen species, reactive nitrogen species, and pro-inflammatory cytokine production and cell death are partly Nrf2 dependent. Mox phenotype is a novel microglial phenotype that has roles in oxidative stress responses. Our results suggested that SFN induced the Mox phenotype in murine microglia through Nrf2 pathway. SFN also alleviated LPS-induced expression of inflammatory microRNA, miR-155. Finally, SFN inhibits microglia-mediated neurotoxicity as demonstrated by conditioned medium and co-culture experiments. In conclusion, SFN exerts protective effects on microglia and modulates the microglial activation state.
Highlights
Microglial cells are the resident macrophages and surveillant cells of the central nervous system (CNS)
We showed that SFN has modulatory effects on the microglial activation state, which results in a state similar to the gene expression pattern of the Mox phenotype
We showed that SFN protected murine microglial cells from LPS-induced cell death
Summary
Microglial cells are the resident macrophages and surveillant cells of the central nervous system (CNS). Various exogenous and endogenous immune stimuli activate microglial cells and start innate immune responses. Microglial activation may result in different outcomes, which are either beneficial or detrimental, depending on the severity and duration of the stimuli. Perpetual overactivation of microglia causes release of various neurotoxic mediators, including reactive oxygen species (ROS), reactive nitrogen species (RNS), and pro-inflammatory cytokines [3]. These mediators result in oxidative stress, neuroinflammation, and mitochondrial dysfunction, thereby leading to loss of surrounding neurons and glial cells. They promote the activation of neighboring microglial cells and microglial toxicity. Persistent activation of glial cells is implicated in the pathogenesis of neurodegenerative diseases [4, 5]
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