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 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.

Microglia-Derived Olfactomedin-like 3 Promotes Pro-Tumorigenic Microglial Function and Malignant Features of Glioma Cells

“…Secreted levels of colony stimulating factor-1 (CSF-1), a cytokine critical for microglial recruitment and glioma growth [ 30 ], were reduced in Olfml3 -/- microglia media compared to isogenic control media following exposure to vehicle (5.5 ± 0.3 vs. 33.8 ± 7, p < 0.01) and TGFβ treatment (β1: 12.6 ± 10 vs. 2.1 ± 0.3, p < 0.05; β2: 17.0 ± 4 vs. 3.2 ± 0.4, p < 0.01; β3: 11.4 ± 1 vs. 2.1 ± 0.4, p = 0.06) ( Figure 4 A). Similar to CSF-1, granulocyte–macrophage colony stimulating factor (GM-CSF) is a key molecule promoting microglial proliferation [ 31 ] and glioma progression [ 32 ]. Under the influence of β1, loss of Olfml3 attenuated secretion of GM-CSF relative to β1-stimulated isogenic control cells (2.2 ± 0.3 vs. 11.9 ± 3; p < 0.05) ( Figure 4 B).…”

Regulation of microglia population dynamics throughout development, health, and disease

“…CSF1R -CSF1 mechanical injection into hippocampus promotes microglial proliferation -De novo neuronal CSF1 promotes microglial proliferation in neuropathic pain -CSF1 hydrogel boosts microglial densities after SCI -CSF1 stimulates microglial proliferation in vitro -CSF1 is necessary for microglia survival in vitro and in vivo (Bellver-Landete et al, 2019;Feng et al, 2019;Giulian & Ingeman, 1988;Gomez-Nicola et al, 2013;Guan et al, 2016;Gushchina et al, 2018;Lee et al, 1993;Okubo et al, 2016;Sawada et al, 1990;Smith et al, 2013;Suzumura et al, 1990;Zhang & Fedoroff, 1998) IL34 CSF1R -IL34 mechanical injection into hippocampus promotes microglial proliferation -IL34 stimulates microglial proliferation in vitro (Gomez-Nicola et al, 2013;Ma et al, 2012;Mizuno et al, 2011;Obst et al, 2020) CSF2/ GM-CSF CSF2R -CSF2 stimulates microglial proliferation in vitro (Calvo et al, 2010;Daria et al, 2017;Dikmen et al, 2020;Gebicke-Haerter et al, 1994;Giulian & Ingeman, 1988;Lee et al, 1993;Lee et al, 1994;Liva & de Vellis, 2001;Suh et al, 2005;Suzumura et al, 1990;Terashima et al, 2018) Aβ/ ApoE/ TREM2 -Trem2 knockout reduces microglial proliferation in APP/PS1, 5xFAD and cuprizone mouse models and hippocampal microglia turnover at homeostasis -Agonistic anti-TREM2 antibodies promote microglial proliferation in 5xFAD mice -TREM2 signaling stimulates microglial proliferation in vitro (Cantoni et al, 2015;Eyo et al, 2018;Jay et al, 2017;Wang et al, 2020;Wang, Ulland, et al, 2016b;…”

Pyridostigmine bromide elicits progressive and chronic impairments in the cholinergic anti-inflammatory pathway in the prefrontal cortex and hippocampus of male rats

“…The GM-CSF findings are particularly interesting as intrahippocampal administration of this cytokine elicits behavioral deficits and activation of microglia in the rat hippocampus ( Zhu et al, 2014 ). Similarly, GM-CSF induces microglia proliferation and the combination of GM-CSF and LPS induces neuroinflammation and increases in oxidative stress in hippocampal organotypic cultures ( Dikmen et al, 2020 ). These results suggest that microglia activation and potentiated neuroinflammatory responses may represent an enduring consequence of PB administration, which provides a potential mechanism for the progressive neurological deficits associated with GWI.…”