Intraperitoneal injection of IL-4/IFN-γ modulates the proportions of microglial phenotypes and improves epilepsy outcomes in a pilocarpine model of acquired epilepsy

Li, Tianyi; Zhai, Xuan; Jiang, Jinqiu; Song, Xiaojie; Han, Wei; Ma, Jianjun; Xie, Lingling; Cheng, Li; Chen, Hengsheng; Jiang, Li

doi:10.1016/j.brainres.2016.12.006

Cited by 34 publications

(40 citation statements)

References 41 publications

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“…These findings also support previous reports indicating in different epilepsy models that microglia M1/M2 polarization plays crucial roles in the pathogenesis of epilepsy [23][24][25]. Although the details of M1/M2 polarization differ from model to model, all these studies show that M1 polarization is increased in the early stage after SE even before myoclonus symptoms, which is consistent with the findings in our study.…”

Section: Morphological Evidence For M1 Mg/mφ Responsesupporting

confidence: 83%

“…Although the details of M1/M2 polarization differ from model to model, all these studies show that M1 polarization is increased in the early stage after SE even before myoclonus symptoms, which is consistent with the findings in our study. M2 polarization has been observed in pilocarpine-induced SE [23,25] and loss-of-function mutations in the cystatin B gene (CSTB) [24] but not in a kainite-induced SE model [23]. M2 microglia were not found to be predominant after pilocarpineinduced SE in our study, which may be due to variations in model establishment, selected time points, and methods used for identifying M1/M2 phenotypes.…”

Section: Morphological Evidence For M1 Mg/mφ Responsementioning

confidence: 56%

“…Neuronal excitotoxicity over a large area produces endogenous damage-associated molecular pattern proteins, such as high mobility group box 1 protein (HMGB-1), which activate MG via TLR4 and other innate immune receptors [7,22]. The relationship between MG/ MΦ polarization and seizure induction has attracted some attention but remains unclear as of yet [23][24][25]. If MG/MΦ polarization could be documented, regulating MG/MΦ polarization toward anti-inflammation would be a therapeutic strategy to address epilepsy by protecting the CNS environment.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of MyD88 Signaling Skews Microglia/Macrophage Polarization and Attenuates Neuronal Apoptosis in the Hippocampus After Status Epilepticus in Mice

Liu

Zhang

et al. 2018

Neurotherapeutics

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Inflammation is implicated in epileptogenesis. Activated microglia and macrophages (MG/MΦ) are found in the brains of patients with epilepsy-related diseases and animal models of epilepsy. It is not yet known how the MG/MΦ activation phenotype affects pathological changes in the brain after a single seizure. In this study, we had 2 main purposes: first, to characterize poststatus epilepticus (SE) inflammation by tracking MG/MΦ polarization, and, second, to explore the role of an innate immune receptor adaptor protein, namely, myeloid differentiation primary response gene 88 (MyD88), in the induction of SE in a mouse model. A lithium-pilocarpine model of seizure conditions was generated in C57BL/6 mice. The intensity and distribution of MG/ MΦ polarization were tracked by fluorescent immunohistochemistry and Western blotting for the polarization markers inducible nitrogen oxygenized synthase, arginase-1, CD163, and mannose receptor. We observed steadily increasing M1 MG/MΦ along with MyD88 signal upregulation after SE in the hippocampi of mice, whereas the M2 marker arginase-1 was localized mainly in astrocytes rather than in MG/MΦ. Inhibition or gene knockout of MyD88 reduced M1 MG/MΦ and gliosis although increasing M2 MG/MΦ in the hippocampi of SE mice. MyD88 inhibition also augmented glutamate transporter 1 expression and reduced N-methyl-D-aspartate receptor NR1 subunit expression in the hippocampus to protect pyramidal neurons from apoptosis. These data suggest that MG/MΦ polarization after SE impacts the pathological outcome of the hippocampus via MyD88 signaling and point to MyD88 as a potential neuroprotective target for epilepsy therapy.

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Section: Morphological Evidence For M1 Mg/mφ Responsesupporting

confidence: 83%

Section: Morphological Evidence For M1 Mg/mφ Responsementioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

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Inhibition of MyD88 Signaling Skews Microglia/Macrophage Polarization and Attenuates Neuronal Apoptosis in the Hippocampus After Status Epilepticus in Mice

Liu

Zhang

et al. 2018

Neurotherapeutics

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“…Delivering IL‐4 (with interferon‐γ) via intraperitoneal injection modified the inflammatory response caused by SE, increasing M2‐like polarization during the acute phase (1‐4 days post‐SE), as well as reducing the M2‐like state (5‐9 days after SE), which led to reduced seizures in the chronic period. However, the exact cellular mechanisms regarding these intriguing outcomes are not known yet and more research is needed in this direction . Nevertheless, the modulation of neuroinflammation by delivery of anti‐inflammatory cytokines to induce M2‐like microglia polarization represents a novel intervention strategy for the management of neuroinflammation following TBI and PTE.…”

Section: Approaches To Induce Microglia M2 Polarization: Potential Agmentioning

confidence: 99%

“…However, the exact cellular mechanisms regarding these intriguing outcomes are not known yet and more research is needed in this direction. 81 Nevertheless, the modulation of neuroinflammation by delivery of anti-inflammatory cytokines to induce M2-like microglia polarization represents a novel intervention strategy for the management of neuroinflammation following TBI and PTE.…”

Section: Exposure To M2-promoting Cytokinesmentioning

confidence: 99%

Microglial polarization in posttraumatic epilepsy: Potential mechanism and treatment opportunity

et al. 2020

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Owing to the complexity of the pathophysiological mechanisms driving epileptogenesis following traumatic brain injury (TBI), effective preventive treatment approaches are not yet available for posttraumatic epilepsy (PTE). Neuroinflammation appears to play a critical role in the pathogenesis of the acquired epilepsies, including PTE, but despite a large preclinical literature demonstrating the ability of anti‐inflammatory treatments to suppress epileptogenesis and chronic seizures, no anti‐inflammatory treatment approaches have been clinically proven to date. TBI triggers robust inflammatory cascades, suggesting that they may be relevant for the pathogenesis of PTE. A major cell type involved in such cascades is the microglial cells—brain‐resident immune cells that become activated after brain injury. When activated, these cells can oscillate between different phenotypes, and such polarization states are associated with the release of various pro‐ and anti‐inflammatory mediators that may influence brain repair processes, and also differentially contribute to the development of PTE. As the molecular mechanisms and key signaling molecules associated with microglial polarization in brain are discovered, strategies are now emerging that can modulate this polarization, promoting this as a potential therapeutic strategy for PTE. In this review, we discuss the relevant literature regarding the polarization of brain‐resident immune cells following TBI and attempt to put into perspective a role in epilepsy pathogenesis. Finally, we explore potential strategies that could polarize microglia/macrophages toward a neuroprotective phenotype to mitigate PTE development.

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Modulation of Microglia M2 Polarization and Alleviation of Hippocampal Neuron Injury By MiR-106b-5p/RGMa in a Mouse Model of Status Epilepticus

Huo

Lei

et al. 2022

Inflammation

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Intraperitoneal injection of IL-4/IFN-γ modulates the proportions of microglial phenotypes and improves epilepsy outcomes in a pilocarpine model of acquired epilepsy

Cited by 34 publications

References 41 publications

Inhibition of MyD88 Signaling Skews Microglia/Macrophage Polarization and Attenuates Neuronal Apoptosis in the Hippocampus After Status Epilepticus in Mice

Inhibition of MyD88 Signaling Skews Microglia/Macrophage Polarization and Attenuates Neuronal Apoptosis in the Hippocampus After Status Epilepticus in Mice

Microglial polarization in posttraumatic epilepsy: Potential mechanism and treatment opportunity

Modulation of Microglia M2 Polarization and Alleviation of Hippocampal Neuron Injury By MiR-106b-5p/RGMa in a Mouse Model of Status Epilepticus

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