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

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-1β. 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. Oxygen-glucose 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.

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