GM-CSF induces noninflammatory proliferation of microglia and disturbs electrical neuronal network rhythms in situ
Abstract Background The granulocyte-macrophage colony-stimulating factor (GM-CSF) (or CSF-2) is involved in myeloid cell growth and differentiation, and, possibly, a major mediator of inflammation in body tissues. The role of GM-CSF in the activation of microglia (CNS resident macrophages) and the c...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-08-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-020-01903-4 |
| _version_ | 1818541690498056192 |
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| author | Hasan Onur Dikmen Marc Hemmerich Andrea Lewen Jan-Oliver Hollnagel Bruno Chausse Oliver Kann |
| author_facet | Hasan Onur Dikmen Marc Hemmerich Andrea Lewen Jan-Oliver Hollnagel Bruno Chausse Oliver Kann |
| author_sort | Hasan Onur Dikmen |
| collection | DOAJ |
| description | Abstract Background The granulocyte-macrophage colony-stimulating factor (GM-CSF) (or CSF-2) is involved in myeloid cell growth and differentiation, and, possibly, a major mediator of inflammation in body tissues. The role of GM-CSF in the activation of microglia (CNS resident macrophages) and the consequent impacts on neuronal survival, excitability, and synaptic transmission are widely unknown, however. Here, we focused on electrical neuronal network rhythms in the gamma frequency band (30–70 Hz). Gamma oscillations are fundamental to higher brain functions, such as perception, attention, and memory, and they are exquisitely sensitive to metabolic and oxidative stress. Methods We explored the effects of chronic GM-CSF exposure (72 h) on microglia in male rat organotypic hippocampal slice cultures (in situ), i.e., postnatal cortex tissue lacking leukocyte invasion (adaptive immunity). We applied extracellular electrophysiological recordings of local field potential, immunohistochemistry, design-based stereology, biochemical analysis, and pharmacological ablation of microglia. Results GM-CSF triggered substantial proliferation of microglia (microgliosis). By contrast, the release of proinflammatory cytokines (IL-6, TNF-α) and nitric oxide, the hippocampal cytoarchitecture as well as the morphology of parvalbumin-positive inhibitory interneurons were unaffected. Notably, GM-CSF induced concentration-dependent, long-lasting disturbances of gamma oscillations, such as slowing (beta frequency band) and neural burst firing (hyperexcitability), which were not mimicked by the T lymphocyte cytokine IL-17. These disturbances were attenuated by depletion of the microglial cell population with liposome-encapsulated clodronate. In contrast to priming with the cytokine IFN-γ (type II interferon), GM-CSF did not cause inflammatory neurodegeneration when paired with the TLR4 ligand LPS. Conclusions GM-CSF has a unique role in the activation of microglia, including the potential to induce neuronal network dysfunction. These immunomodulatory properties might contribute to cognitive impairment and/or epileptic seizure development in disease featuring elevated GM-CSF levels, blood-brain barrier leakage, and/or T cell infiltration. |
| first_indexed | 2024-12-11T22:12:31Z |
| format | Article |
| id | doaj.art-2a802789226b4121af84840fce089437 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-11T22:12:31Z |
| publishDate | 2020-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-2a802789226b4121af84840fce0894372022-12-22T00:48:43ZengBMCJournal of Neuroinflammation1742-20942020-08-0117111310.1186/s12974-020-01903-4GM-CSF induces noninflammatory proliferation of microglia and disturbs electrical neuronal network rhythms in situHasan Onur Dikmen0Marc Hemmerich1Andrea Lewen2Jan-Oliver Hollnagel3Bruno Chausse4Oliver Kann5Institute of Physiology and Pathophysiology, University of HeidelbergInstitute of Physiology and Pathophysiology, University of HeidelbergInstitute of Physiology and Pathophysiology, University of HeidelbergInstitute of Physiology and Pathophysiology, University of HeidelbergInstitute of Physiology and Pathophysiology, University of HeidelbergInstitute of Physiology and Pathophysiology, University of HeidelbergAbstract Background The granulocyte-macrophage colony-stimulating factor (GM-CSF) (or CSF-2) is involved in myeloid cell growth and differentiation, and, possibly, a major mediator of inflammation in body tissues. The role of GM-CSF in the activation of microglia (CNS resident macrophages) and the consequent impacts on neuronal survival, excitability, and synaptic transmission are widely unknown, however. Here, we focused on electrical neuronal network rhythms in the gamma frequency band (30–70 Hz). Gamma oscillations are fundamental to higher brain functions, such as perception, attention, and memory, and they are exquisitely sensitive to metabolic and oxidative stress. Methods We explored the effects of chronic GM-CSF exposure (72 h) on microglia in male rat organotypic hippocampal slice cultures (in situ), i.e., postnatal cortex tissue lacking leukocyte invasion (adaptive immunity). We applied extracellular electrophysiological recordings of local field potential, immunohistochemistry, design-based stereology, biochemical analysis, and pharmacological ablation of microglia. Results GM-CSF triggered substantial proliferation of microglia (microgliosis). By contrast, the release of proinflammatory cytokines (IL-6, TNF-α) and nitric oxide, the hippocampal cytoarchitecture as well as the morphology of parvalbumin-positive inhibitory interneurons were unaffected. Notably, GM-CSF induced concentration-dependent, long-lasting disturbances of gamma oscillations, such as slowing (beta frequency band) and neural burst firing (hyperexcitability), which were not mimicked by the T lymphocyte cytokine IL-17. These disturbances were attenuated by depletion of the microglial cell population with liposome-encapsulated clodronate. In contrast to priming with the cytokine IFN-γ (type II interferon), GM-CSF did not cause inflammatory neurodegeneration when paired with the TLR4 ligand LPS. Conclusions GM-CSF has a unique role in the activation of microglia, including the potential to induce neuronal network dysfunction. These immunomodulatory properties might contribute to cognitive impairment and/or epileptic seizure development in disease featuring elevated GM-CSF levels, blood-brain barrier leakage, and/or T cell infiltration.http://link.springer.com/article/10.1186/s12974-020-01903-4CytokinesElectrophysiologyGM-CSFHippocampusInnate immunityMicroglia |
| spellingShingle | Hasan Onur Dikmen Marc Hemmerich Andrea Lewen Jan-Oliver Hollnagel Bruno Chausse Oliver Kann GM-CSF induces noninflammatory proliferation of microglia and disturbs electrical neuronal network rhythms in situ Journal of Neuroinflammation Cytokines Electrophysiology GM-CSF Hippocampus Innate immunity Microglia |
| title | GM-CSF induces noninflammatory proliferation of microglia and disturbs electrical neuronal network rhythms in situ |
| title_full | GM-CSF induces noninflammatory proliferation of microglia and disturbs electrical neuronal network rhythms in situ |
| title_fullStr | GM-CSF induces noninflammatory proliferation of microglia and disturbs electrical neuronal network rhythms in situ |
| title_full_unstemmed | GM-CSF induces noninflammatory proliferation of microglia and disturbs electrical neuronal network rhythms in situ |
| title_short | GM-CSF induces noninflammatory proliferation of microglia and disturbs electrical neuronal network rhythms in situ |
| title_sort | gm csf induces noninflammatory proliferation of microglia and disturbs electrical neuronal network rhythms in situ |
| topic | Cytokines Electrophysiology GM-CSF Hippocampus Innate immunity Microglia |
| url | http://link.springer.com/article/10.1186/s12974-020-01903-4 |
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