Zinc Triggers Microglial Activation
Open accessAbstract
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-κB (NF-κB) reporter gene showed a severalfold increase in NF-κB activity in response to 30 μ m zinc. Cultured mouse microglia exposed to 15–30 μ 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-κB 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-κB. These findings identify a novel trigger for microglial activation and a previously unrecognized mechanism by which zinc may contribute to neurological disorders.
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Inhibiting PARP-1 suppresses microglial activation likely via regulating NF-kB-dependent gene transcription.
“Inhibiting PARP-1 suppresses microglial activation likely via regulating NF-kB-dependent gene transcription.523”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [523]
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Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets
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Self-citationA Neurotoxic Ménage-à-trois: Glutamate, Calcium, and Zinc in the Excitotoxic Cascade
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- Authors
- Kauppinen, T. M., Higashi, Y., Suh, S. W., Escartin, C., Nagasawa, K., & Swanson, R. A.
- Affiliations
- San Francisco VA Medical Center (US)
- Centre National de la Recherche Scientifique (FR)
- University of California, San Francisco (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-05-28
- Volume
- 28
- Issue
- 22
- Pages
- 5827-5835
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2680357
- OpenAlex
- W1969927114
- Cited by
- 174
- References
- 69
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 4 · 2023: 12 · 2022: 8 · 2021: 5 · 2020: 11 · 2019: 11 · 2018: 10 · 2017: 11 · 2016: 7 · 2015: 7 · 2014: 17 · 2013: 14 · 2012: 14
- FWCI
- 6.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- HAL (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (P50NS014543, NS145434, R01NS041421)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- zinc, microglial activation, NF-κB, NADPH oxidase, PARP1, nitric oxide, cerebral ischemia-reperfusion injury, zinc chelation, CaEDTA, neuroinflammation, neuronal cell death, neurodegenerative diseases
- MeSH terms
- Poly (ADP-Ribose) Polymerase-1, ATPases Associated with Diverse Cellular Activities, Animals, Animals, Newborn, Antigens, Differentiation, Cell Survival, Cells, Cultured, Cerebral Cortex, Ischemic Attack, Transient, DNA Helicases, Dose-Response Relationship, Drug, Mice, Inbred C57BL, Nitric Oxide, Phenanthrenes, Poly(ADP-ribose) Polymerases, Trace Elements, Zinc, Cytokines, NF-kappa B, Prosencephalon, Reactive Oxygen Species, Microglia, Mice, Knockout, NADPH Oxidases, Mice
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