The voltage‐gated potassium channel Kv1.3 is required for microglial pro‐inflammatory activation in vivo
Open accessAbstract
Microglia show a rich repertoire of activation patterns regulated by a complex ensemble of surface ion channels, receptors, and transporters. We and others have investigated whether microglia vary their K + channel expression as a means to achieve functional diversity. However, most of the prior studies were conducted using in vitro models such as BV2 cells, primary microglia, or brain slices in culture, which may not accurately reflect microglia physiology in adult individuals. Here we employed an in vivo mouse model of selective innate immune activation by intracerebroventricular injection of lipopolysaccharides (ICV‐LPS) to determine the role of the voltage‐gated Kv1.3 channel in LPS‐induced M1‐like microglial activation. Using microglia acutely isolated from adult brains, we detected Kv1.3 and Kir2.1 currents, and found that ICV‐LPS increased the current density and RNA expression of Kv1.3 but did not affect those of Kir2.1. Genetic knockout of Kv1.3 abolished LPS‐induced microglial activation exemplified by Iba‐1 immunoreactivity and expression of pro‐inflammatory mediators such as IL‐1β, TNF‐α, IL‐6, and iNOS. Moreover, Kv1.3 knockout mitigated the LPS‐induced impairment of hippocampal long‐term potentiation (hLTP), suggesting that Kv1.3 activity regulates pro‐inflammatory microglial neurotoxicity. Pharmacological intervention using PAP‐1, a small molecule that selectively blocks homotetrameric Kv1.3 channels, achieved anti‐inflammatory and hLTP‐recovery effects similar to Kv1.3 knockout. We conclude that Kv1.3 is required for microglial M1‐like pro‐inflammatory activation in vivo . A significant implication of our in vivo data is that Kv1.3 blockers could be therapeutic candidates for neurological diseases where microglia‐mediated neurotoxicity is implicated in the pathogenesis.
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Outward K+ current is largely mediated by voltage-gated K+ channels, particularly Kv1.3, which critically regulates proinflammatory cytokine generation.
“and is largely mediated by voltage-gated K+ channels, particularly Kv1.3, which critically regulates proinflammatory cytokine generation (Di Lucente et al., 2018).”
From Overexpressing low‐density lipoprotein receptor reduces tau‐associated neurodegeneration in relation to apoE‐linked mechanisms (2021) · cites this paper as Di Lucente et al., 2018
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Cites
Structural and functional features of central nervous system lymphatic vessels
Louveau, A., Smirnov, I., Keyes, T. J., Eccles, J. D., Rouhani, S. J., Peske, J. D., Derecki, N. C., Castle, D., Mandell, J. W., Lee, K. S., et al. (2015) · Nature · doi:10.1038/nature14432 · Cited by 4,413 · see citing works
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Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice
Villeda, S. A., Plambeck, K. E., Middeldorp, J., Castellano, J. M., Mosher, K. I., Luo, J., Smith, L. K., Bieri, G., Lin, K., Berdnik, D., et al. (2014) · Nature Medicine · doi:10.1038/nm.3569 · Cited by 1,081 · see citing works
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Macrophages in inflammatory multiple sclerosis lesions have an intermediate activation status
Vogel, D. Y., Vereyken, E. J., Glim, J. E., Heijnen, P. D., Moeton, M., van der Valk, P., Amor, S., Teunissen, C. E., van Horssen, J., & Dijkstra, C. D. (2013) · Journal of Neuroinflammation · doi:10.1186/1742-2094-10-35 · Cited by 479 · see citing works
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“Microglia were isolated using CD11b-based immunopanning as previously described (Bohlen et al., 2017; Jin et al., 2015).”
MethodBlockade of Kv1.3 channels ameliorates radiation-induced brain injury
Peng, Y., Lu, K., Li, Z., Zhao, Y., Wang, Y., Hu, B., Xu, P., Shi, X., Zhou, B., Pennington, M., et al. (2014) · Neuro-Oncology · doi:10.1093/neuonc/not221 · Cited by 78 · see citing works
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Shi, Y., Andhey, P. S., Ising, C., Wang, K., Snipes, L. L., Boyer, K., Lawson, S., Yamada, K., Qin, W., Manis, M., et al. (2021) · Neuron · doi:10.1016/j.neuron.2021.05.034 · Cited by 135 · see citing works
- Authors
- Di Lucente, J., Nguyen, H. M., Wulff, H., Jin, L., & Maezawa, I.
- Affiliations
- From the Department of Pathology and Laboratory Medicine and M.I.N.D. Institute University of California Davis Medical Center Sacramento California
- University of California, Davis (US)
- University of California Davis Medical Center (US)
- Corresponding author
- Maezawa, Izumi
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2018-07-25
- Volume
- 66
- Issue
- 9
- Pages
- 1881-1895
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- PMC
- PMC6185766
- OpenAlex
- W2883704778
- Cited by
- 96
- References
- 8
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 16 · 2023: 9 · 2022: 16 · 2021: 16 · 2020: 18 · 2019: 5
- FWCI
- 4.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Glia (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS100294)
- Alzheimer's Association (NIRG‐10‐174150)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Kv1.3 potassium channel, microglial activation, lipopolysaccharide, innate immune activation, microglial neurotoxicity, hippocampal long-term potentiation, PAP1, Kir2.1, inflammatory cytokines, anti-inflammatory therapy
- MeSH terms
- Animals, Brain, Calcium-Binding Proteins, Escherichia coli, Immunity, Innate, Inflammation, Lipopolysaccharides, Mice, Inbred C57BL, Microfilament Proteins, Cytokines, Microglia, Long-Term Potentiation, Mice, Knockout, Potassium Channels, Inwardly Rectifying, Tissue Culture Techniques, Kv1.3 Potassium Channel
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