Quercetin Attenuates Inflammatory Responses in BV-2 Microglial Cells: Role of MAPKs on the Nrf2 Pathway and Induction of Heme Oxygenase-1

Abstract

A large group of flavonoids found in fruits and vegetables have been suggested to elicit health benefits due mainly to their anti-oxidative and anti-inflammatory properties. Recent studies with immune cells have demonstrated inhibition of these inflammatory responses through down-regulation of the pro-inflammatory pathway involving NF-κB and up-regulation of the anti-oxidative pathway involving Nrf2. In the present study, the murine BV-2 microglial cells were used to compare anti-inflammatory activity of quercetin and cyanidin, two flavonoids differing by their alpha, beta keto carbonyl group. Quercetin was 10 folds more potent than cyanidin in inhibition of lipopolysaccharide (LPS)-induced NO production as well as stimulation of Nrf2-induced heme-oxygenase-1 (HO-1) protein expression. In addition, quercetin demonstrated enhanced ability to stimulate HO-1 protein expression when cells were treated with LPS. In an attempt to unveil mechanism(s) for quercetin to enhance Nrf2/HO-1 activity under endotoxic stress, results pointed to an increase in phospho-p38MAPK expression upon addition of quercetin to LPS. In addition, pharmacological inhibitors for phospho-p38MAPK and MEK1/2 for ERK1/2 further showed that these MAPKs target different sites of the Nrf2 pathway that regulates HO-1 expression. However, inhibition of LPS-induced NO by quercetin was not fully reversed by TinPPIX, a specific inhibitor for HO-1 activity. Taken together, results suggest an important role of quercetin to regulate inflammatory responses in microglial cells and its ability to upregulate HO-1 against endotoxic stress through involvement of MAPKs.

Effects of Dietary Flavonoids on Reverse Cholesterol Transport, HDL Metabolism, and HDL function

“…Flavonoids may positively influence health through their well-documented effects on cellular antioxidant status and inflammation (68). Flavonoids may augment endogenous antioxidant defenses through nuclear factor, erythroid 2-like 2 (Nrf2) activation of antioxidant response elements of genes encoding antioxidant enzymes in vitro (69,70). Anthocyanin intake has been shown to reduce systemic inflammation markers in humans while also suppressing LPS activation of NF-kB in human monocytes (71).…”

Botanical Polyphenols Mitigate Microglial Activation and Microglia-Induced Neurotoxicity: Role of Cytosolic Phospholipase A2

“…2a-c). The indicated concentrations of quercetin, honokiol, and C3G had been discussed to pose no toxicity to BV-2 cells in previous studies Sun et al 2015;Kaushik et al 2012). Fig.…”

“…Previous studies from our laboratory as well as from others have demonstrated the effects of botanicals, such as quercetin from berries and honokiol from the magnolia bark, to mitigate microglial-induced production of NO and reactive oxygen species (ROS) upon stimulation by LPS or pro-inflammatory cytokines (Chuang et al 2013;Jiang et al 2014). These studies also unveil differences in potency in their ability to mitigate antioxidative and anti-inflammatory responses Sun et al 2015).…”

Western lifestyle and immunopathology of multiple sclerosis

“…Quercetin and epigallocatechin gallate (EGCG) reduce the production of proinflammatory cytokines by macrophages and microglia 142, 143, 144, 145. Moreover, flavonoids, such as quercetin, suppress the capacity of monocytes to cross the BBB and limit the uptake of myelin by macrophages 146, 147.…”