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  • Quercetin hinders microglial activation to alleviate neurotoxicity via the interplay between NLRP3 inflammasome and mitophagy.

Quercetin hinders microglial activation to alleviate neurotoxicity via the interplay between NLRP3 inflammasome and mitophagy.

Redox biology (2021-06-04)
Xiaojuan Han, Tianshu Xu, Qijun Fang, Huajun Zhang, Lijun Yue, Gang Hu, Lingyun Sun
ABSTRACT

Activated microglia are an important type of innate immune cell in the brain, and they secrete inflammatory cytokines into the extracellular milieu, exert neurotoxicity to surrounding neurons and are involved in the pathogenesis of many brain disorders. Quercetin (Qu), a natural flavonoid, is known to have anti-inflammatory and antioxidant properties. Previous studies have shown that both increased reactive oxygen species (ROS) stress and decreased autophagy participate in the activation of microglial. In the current study, we showed that Qu significantly attenuated LPS-induced inflammatory factor production, cell proliferation and NF-κB activation of microglia. Importantly, Qu decreased the levels of NLR family, pyrin domain containing three (NLRP3) inflammasome and pyroptosis-related proteins, including NLRP3, active caspase-1, GSDMD N-terminus and cleaved IL-1β. Further study indicated that this anti-inflammatory effect of Qu was associated with mitophagy regulation. Importantly, Qu promoted mitophagy to enhance damaged mitochondrial elimination, which then reduced mtROS accumulation and alleviated NLRP3 inflammasome activation. Then, we confirmed that Qu treatment protected primary neurons against LPS-induced microglial toxicity and alleviated neurodegeneration in both depression and PD mouse models. Further IL-1β administration blunted these neuroprotective effects of Qu in vitro and in vivo. This work illustrated that Qu prevents neuronal injury via inhibition of mtROS-mediated NLRP3 inflammasome activation in microglia through promoting mitophagy, which provides a potential novel therapeutic strategy for neuroinflammation-related diseases.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-GSDMD (126-138) antibody produced in rabbit, IgG fraction of antiserum, buffered aqueous solution
Sigma-Aldrich
Monoclonal Anti-Tyrosine Hydroxylase antibody produced in mouse, clone TH-2, ascites fluid
Sigma-Aldrich
Anti-IL-1 β Antibody, Chemicon®, from rabbit