Zinc Triggers Microglial Activation

Abstract

Microglia are resident immune cells of the CNS. When stimulated by infection, tissue injury, or other signals, microglia assume an activated, "ameboid" morphology and release matrix metalloproteinases, reactive oxygen species, and other proinflammatory factors. This innate immune response augments host defenses, but it can also contribute to neuronal death. Zinc is released by neurons under several conditions in which microglial activation occurs, and zinc chelators can reduce neuronal death in animal models of cerebral ischemia and neurodegenerative disorders. Here, we show that zinc directly triggers microglial activation. Microglia transfected with a nuclear factor-B (NF-B) reporter gene showed a severalfold increase in NF-B activity in response to 30 M zinc. Cultured mouse microglia exposed to 15-30 M zinc increased nitric oxide production, increased F4/80 expression, altered cytokine expression, and assumed the activated morphology. Zinc-induced microglial activation was blocked by inhibiting NADPH oxidase, poly(ADP-ribose) polymerase-1 (PARP-1), or NF-B activation. Zinc injected directly into mouse brain induced microglial activation in wild-type mice, but not in mice genetically lacking PARP-1 or NADPH oxidase activity. Endogenous zinc release, induced by cerebral ischemia-reperfusion, likewise induced a robust microglial reaction, and this reaction was suppressed by the zinc chelator CaEDTA. Together, these results suggest that extracellular zinc triggers microglial activation through the sequential activation of NADPH oxidase, PARP-1, and NF-B. These findings identify a novel trigger for microglial activation and a previously unrecognized mechanism by which zinc may contribute to neurological disorders.

Microglial Activation in Stroke: Therapeutic Targets

“…Superoxide and these other reactive species also promote microglial activation in a feed-forward manner. 21,22 The production of superoxide by microglia occurs primarily by NADPH oxidase (NOX), of which several isoforms have been characterized. 23,24 Of note, glucose availability can be rate-limiting for NADPH production, and thus for superoxide production, and this provides a mechanism by which hyperglycemia can exacerbate injury during ischemia or inflammation.…”

“…Zinc has been shown to induce activation of microglia in culture and in brain, and injection of the zinc chelator CaEDTA prevents ischemia-induced microglial activation. 22 The mechanism of this effect appears linked to the more general effect of oxidant stress on microglial and macrophage activation. 21 Zinc has been shown to upregulate NADPH oxidase in these cells, and the effect of zinc on microglial activation is blocked in the absence of NADPH oxidase activity.…”

“…21 Zinc has been shown to upregulate NADPH oxidase in these cells, and the effect of zinc on microglial activation is blocked in the absence of NADPH oxidase activity. 22 The effect of zinc is also blocked by inhibiting activation of poly(ADP-ribose) polymerase 1 (PARP-1) or translocation of NF-B translocation, thus linking the zinc effect to established pathways of microglial activation. 22 …”

“…22 The effect of zinc is also blocked by inhibiting activation of poly(ADP-ribose) polymerase 1 (PARP-1) or translocation of NF-B translocation, thus linking the zinc effect to established pathways of microglial activation. 22 …”

Prevention of Acute/Severe Hypoglycemia-Induced Neuron Death by Lactate Administration

“…Three sections from each animal were evaluated for scoring. Microglial activation criteria were based on the number of CD11b immunoreactive cells and their morphology (Kauppinen et al, 2008).…”