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Improved 3D Hydrogel Cultures of Primary Glial Cells for In Vitro Modelling of Neuroinflammation
Published on: December 8, 2017
Interaction between astrocytic colony stimulating factor and its receptor on microglia mediates central sensitization
Yuying Tang1, Lian Liu2, Dan Xu2
1Department of Anesthesiology, West China Second Hospital, Sichuan University, Chengdu, Sichuan, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China.
Abstract:
Accumulation of microglia occurs in the dorsal horn in the rodent model of chronic post ischemic pain (CPIP), while the mechanism how microglia affects the development of persistent pain largely remains unknown. Here, using a rodent model of CPIP induced by ischemia-reperfusion (IR) injury in the hindpaw, we observed that microglial accumulation occurred in the ipsilateral dorsal horn after ischemia 3h, and in ipsilateral and contralateral dorsal horn in the rats with ischemia 6h. The accumulated microglia released BDNF, increased neuronal excitability in dorsal horn, and produced pain behaviors in the modeled rodents. We also found significantly increased signaling mediated by astrocytic colony-stimulating factor-1 (CSF1) and microglial CSF1 receptor (CSF1R) in dorsal horn in the ischemia 6h modeled rats. While exogenous M-CSF induced microglial activation and proliferation, BDNF production, neuronal hyperactivity in dorsal horn and behavioral hypersensitivity in the naïve rats, inhibition of astrocytic CSF1/microglial CSF1R signaling by fluorocitric or PLX3397 significantly suppressed microglial activation and proliferation, BDNF upregulation, and neuronal activity in dorsal horn, as well as the mechanical allodynia and thermal hyperalgesia, in the rats with ischemia 6h. Collectively, these results demonstrated that glial CSF1/CSF1R pathway mediated the microglial activation and proliferation, which facilitated the nociceptive output and contributed to the chronic pain induced by IR injury.
Insights
Microglia accumulation in the dorsal horn drives chronic pain after ischemia-reperfusion injury. Targeting the CSF1/CSF1R pathway reduces microglial activation, neuronal excitability, and pain behaviors.
Area of Science:
- Neuroscience
- Pain Research
- Cellular Biology
Background:
- Chronic post-ischemic pain (CPIP) involves microglial accumulation in the dorsal horn.
- The precise mechanisms by which microglia contribute to persistent pain remain unclear.
Purpose of the Study:
- To investigate the role of microglia and the CSF1/CSF1R pathway in the development of CPIP.
- To elucidate the cellular and molecular mechanisms underlying pain persistence after ischemia-reperfusion (IR) injury.
Main Methods:
- Utilized a rodent model of CPIP induced by hindpaw ischemia-reperfusion (IR) injury.
- Observed microglial accumulation and activation in the dorsal horn at different time points post-IR.
- Assessed the effects of modulating the astrocytic CSF1/microglial CSF1R signaling pathway using pharmacological inhibitors (fluorocitric acid, PLX3397).
- Measured neuronal excitability, BDNF levels, and pain behaviors (mechanical allodynia, thermal hyperalgesia).
Main Results:
- Microglial accumulation and BDNF release were observed in the dorsal horn following IR injury, correlating with increased neuronal excitability and pain behaviors.
- Significantly elevated astrocytic CSF1 and microglial CSF1R signaling were detected in the dorsal horn of rats with CPIP.
- Exogenous M-CSF induced microglial activation, BDNF production, and hypersensitivity in naive rats.
- Inhibition of the CSF1/CSF1R pathway suppressed microglial activation, BDNF upregulation, neuronal hyperactivity, and alleviated pain behaviors in CPIP rats.
Conclusions:
- The glial CSF1/CSF1R pathway is crucial for mediating microglial activation and proliferation in the context of CPIP.
- This pathway facilitates nociceptive output and contributes significantly to the development and maintenance of chronic pain following IR injury.
