Role of zinc dyshomeostasis in inflammasome formation in cultured cortical cells following lipopolysaccharide or oxygen-glucose deprivation/reperfusion exposure

NEUROBIOLOGY OF DISEASE

卷:137

Article

Park, Hyun-Seo¹  Yoo, Min Heui²  Koh, Jae-Young^1,3 

[1] Univ Ulsan, Asan Inst Life Sci, Coll Med, Neural Injury Res Ctr, Ulsan, South Korea

[2] Korea Inst Toxicol, Dept Innovat Toxicol Res, Daejeon, South Korea

[3] Asan Med Ctr, Dept Neurol, Seoul, South Korea

关键词: Zinc;    Ischemic stroke;    LPS;    Oxygen-glucose deprivation/reperfusion;    NLRP3 inflammasome;    Secondary brain injury;   

DOI  :  10.1016/j.nbd.2020.104771

来源: Elsevier

【 摘 要 】

Exposure of mouse mixed cortical cell cultures to lipopolysaccharide (LPS) resulted in inflammasome formation in neurons and astrocytes, as indicated by increases in the levels of NLRP3, ASC, caspase-1, and IL-1 beta. LPS exposure concurrently increased the level of free zinc in the cytosol of both cell types. Addition of the membrane-permeant zinc chelator TPEN blocked the increases in the levels of NLRP3 and caspase-1 as well as the release of inflammatory cytokines, indicating a role for increased zinc in LPS-induced inflammasome formation. Oxygenglucose deprivation (OGD), a cellular model of hypoxia, also induced inflammasome formation and zinc dyshomeostasis in cortical cells, effects that were abolished upon zinc chelation with TPEN. A similar mechanism appeared to be at work in vivo. Whereas intraperitoneal injection of LPS in mice resulted in inflammasome formation and microglial activation in the brain, it caused little induction of inflammasome formation in ZnT3-null mice, which lack synaptic zinc, suggesting a specific role for synaptic zinc in LPS-induced formation of inflammasomes in the mouse brain.