Complex alterations in microglial M1/M2 markers during the development of epilepsy in two mouse models
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Summary: Objective: To characterize the changes in microglial proinflammatory M1 and antiinflammatory M2 marker expression during epileptogenesis in the chronic pilocarpine and intrahippocampal kainate models. Methods: M1‐activated microglia express proinflammatory cytokines driving infiltration of cells, whereas M2‐activated microglia are more reparative, promoting phagocytosis of debris and expression of proteins associated with cellular stability and repair. Microglial markers were characterized as acute (3 days after status epilepticus [SE]), early chronic (21 days post‐SE), and late chronic epileptic (5–12 months post‐SE) time points. Following pilocarpine‐SE, microglial markers were assessed by flow cytometry. Quantitative real‐time polymerase chain reaction (RT‐PCR) was used to measure messenger RNA (m RNA) levels of selected M1 (interleukin [IL] 1β, tumor necrosis factor α [TNF α] cluster of differentiation [CD],CD16, and CD86), interleukin‐6 [IL‐6], interleukin‐12 [IL‐12], Fc receptors 16, and CD 86) and M2 (arginase 1 [Arg1], chitinase‐3‐like protein [Ym1], found in inflammatory zone [FIZZ‐1] [FIZZ‐1], mannose receptor C type‐1 [CD206], interleukin‐4 [IL‐4], and interleukin‐10 (IL‐10)) markers in both models. Video–electroencephalography (EEG) recordings were used to quantify late chronic seizure frequency. Results: Three days post‐SE microglia in the pilocarpine model expressed M1 and M2 markers, but only M1 markers were upregulated after kainate‐induced SE. After 3 weeks, M1/M2 marker expression was largely ablated in the hippocampal formation of both models. Small m RNA level increases of CD 11b, glial fibrillary acidic protein (GFAP), and IL‐1β were found in the pilocarpine model, consistent with IL‐1β contributing to spontaneous seizures, whereas m RNA levels of TNF α and Ym1 were decreased. In the late chronic phase, some M1/M2 markers, IL‐1β, TNF α, Arg1, Ym1, and CD 206, resurged in the kainate, but not pilocarpine model, which may reflect and/or contribute to highly frequent seizures in kainate‐SE mice. Significance: The common M1 upregulation acutely post‐SE may signal a role early in epileptogenesis, with a more pure “inflamed” central nervous system state after kainate‐SE, potentially contributing to the development of more frequent seizures. The difference may also be due to the contribution of peripheral inflammation after pilocarpine injection. In summary, the microglial inflammatory response during epileptogenesis is complex, varies between models, and appears to correlate with chronic seizure frequency.
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In animal models, seizures are associated with increased activation of microglia, especially the M1 subtype, and increased release of pro-inflammatory mediators.
“Studies in animal models have reported that seizures are associated with increased activation of microglia, especially of the M1 subtype [189], and an increased release of pro-inflammatory mediators [190, 191].”
From Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation (2019) · cites this paper as [189]
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Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation
Lima Giacobbo, B., Doorduin, J., Klein, H. C., Dierckx, R. A. J. O., Bromberg, E., & de Vries, E. F. J. (2019) · Molecular Neurobiology · doi:10.1007/s12035-018-1283-6 · Cited by 750 · see citing works
- Authors
- Benson, M. J., Manzanero, S., & Borges, K.
- Affiliations
- The University of Queensland (AU)
- Corresponding author
- Borges, Karin
- Venue
- Epilepsia
- Publisher
- Wiley
- Published
- 2015-04-03
- Volume
- 56
- Issue
- 6
- Pages
- 895-905
- ISSN
- 0013-9580 (ISSN-L)
- 1528-1167
- OpenAlex
- W1979575851
- Cited by
- 176
- References
- 45
- Citations by year
- 2026: 15 · 2025: 18 · 2024: 18 · 2023: 21 · 2022: 19 · 2021: 23 · 2020: 19 · 2019: 10 · 2018: 11 · 2017: 11 · 2016: 10 · 2015: 1
- FWCI
- 8.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Epilepsia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Australian National Health and Medical Research Council (63145, 1044407, 1057846)
- Australian Rotary Health and the Rotary Club of Koo Wee Rup Lang Lang
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- microglia, macrophage polarization, epileptogenesis, status epilepticus, pilocarpine model, kainate model, hippocampus, IL-1β, TNF-α, arginase-1, Ym1, CD206, CD86, CD16, CD11b, spontaneous seizures, neuroinflammation
- MeSH terms
- Analysis of Variance, Animals, Arginase, beta-N-Acetylhexosaminidases, Convulsants, Disease Models, Animal, Epilepsy, Flow Cytometry, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Hippocampus, Kainic Acid, Male, Pilocarpine, Time Factors, Cytokines, Microglia, Lectins, Mice
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