Abstract |
Microglia are highly plastic cells that can assume different phenotypes in response to microenvironmental signals. Lipopolysaccharide (LPS) and interferon-γ (IFN-γ) promote differentiation into classically activated M1-like microglia, which produce high levels of pro-inflammatory cytokines and nitric oxide and are thought to contribute to neurological damage in ischemic stroke and Alzheimer's disease. IL-4 in contrast induces a phenotype associated with anti-inflammatory effects and tissue repair. We here investigated whether these microglia subsets vary in their K+ channel expression by differentiating neonatal mouse microglia into M(LPS) and M(IL-4) microglia and studying their K+ channel expression by whole-cell patch-clamp, quantitative PCR and immunohistochemistry. We identified three major types of K+ channels based on their biophysical and pharmacological fingerprints: a use-dependent, outwardly rectifying current sensitive to the KV 1.3 blockers PAP-1 and ShK-186, an inwardly rectifying Ba2+ -sensitive Kir 2.1 current, and a Ca2+ -activated, TRAM-34-sensitive KCa 3.1 current. Both KV 1.3 and KCa 3.1 blockers inhibited pro-inflammatory cytokine production and iNOS and COX2 expression demonstrating that KV 1.3 and KCa 3.1 play important roles in microglia activation. Following differentiation with LPS or a combination of LPS and IFN-γ microglia exhibited high KV 1.3 current densities (∼50 pA/pF at 40 mV) and virtually no KCa 3.1 and Kir currents, while microglia differentiated with IL-4 exhibited large Kir 2.1 currents (∼ 10 pA/pF at -120 mV). KCa 3.1 currents were generally low but moderately increased following stimulation with IFN-γ or ATP (∼10 pS/pF). This differential K+ channel expression pattern suggests that KV 1.3 and KCa 3.1 inhibitors could be used to inhibit detrimental neuroinflammatory microglia functions. GLIA 2016;65:106-121.
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Authors | Hai M Nguyen, Eva M Grössinger, Makoto Horiuchi, Kyle W Davis, Lee-Way Jin, Izumi Maezawa, Heike Wulff |
Journal | Glia
(Glia)
Vol. 65
Issue 1
Pg. 106-121
(01 2017)
ISSN: 1098-1136 [Electronic] United States |
PMID | 27696527
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | © 2016 The Authors. Glia Published by Wiley Periodicals, Inc. |
Chemical References |
- Intermediate-Conductance Calcium-Activated Potassium Channels
- Kcnn4 protein, mouse
- Kir2.1 channel
- Kv1.3 Potassium Channel
- Lipopolysaccharides
- Potassium Channels, Inwardly Rectifying
- Interferon-gamma
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Topics |
- Animals
- Cells, Cultured
- Interferon-gamma
(metabolism)
- Intermediate-Conductance Calcium-Activated Potassium Channels
(metabolism)
- Kv1.3 Potassium Channel
(metabolism)
- Lipopolysaccharides
(pharmacology)
- Macrophage Activation
- Membrane Potentials
- Mice, Inbred C57BL
- Microglia
(metabolism)
- Potassium Channels, Inwardly Rectifying
(metabolism)
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