Positive Feedback Loop of Autocrine BDNF from Microglia Causes Prolonged Microglia Activation

Abstract

Background/Aims: Microglia, which represent the immune cells of the central nervous system (CNS), have long been a subject of study in CNS disease research. Substantial evidence indicates that microglial activation functions as a strong neuro-inflammatory response in neuropathic pain, promoting the release of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α. In addition, activated microglia release brain-derived neurotrophic factor (BDNF), which acts as a powerful cytokine. In this study, we performed a series of in vitro experiments to examine whether a positive autocrine feedback loop existed between microglia-derived BDNF and subsequent microglial activation as well as the mechanisms underlying this positive feedback loop. Methods: Because ATP is a classic inducer of microglial activation, firstly, we examined ATP-activated microglia in the present study. Secondly, we used TrkB/Fc, the BDNF sequester, to eliminate the effects of endogenous BDNF. ATP-stimulated microglia without BDNF was examined. Finally, we used exogenous BDNF to further determine whether BDNF could directly activate BV2 microglia. In all experiments, to quantify BV2 microglia activation, the protein levels of CD11b, a microglial activation marker, were measured by western blot. A Transwell migration assay was used to examine microglial migration. To assess the synthesis and release of proinflammatory cytokines, western blot was used to measure BDNF synthesis, and ELISA was used to quantify TNF-α release. Results: In our present research, we have observed that ATP dramatically activates microglia, enhancing microglial migration, increasing the synthesis of BDNF and up-regulating the release of TNF-α. Microglial activation is inhibited following the sequestration of endogenous BDNF, resulting in impaired microglial migration and decreased TNF-α release. Furthermore, exogenous BDNF can also activate microglia to subsequently enhance migration and increase TNF-α release. Conclusion: Therefore, we suggest that microglial activation increases the synthesis of BDNF and that the release of BDNF can, in turn, activate microglia. A positive autocrine BDNF feedback loop from microglia may contribute to prolonged microglial activation.

Induction of Microglial Activation by Mediators Released from Mast Cells

“…Our in vivo study showed that S100A8 resulted in microglial activation following the occurrence and development of surgery-induced neuroinflammation and cognitive dysfunction [36]. Activated microglia can release BDNF, which causes prolonged microglial activation [37]. Therefore, the inhibition of microglial activation and subsequent neuroinflammation may offer prospective clinical therapeutic benefits for neuroinflammation-related neurodegenerative disorders.…”

Cognitive impairments following cranial irradiation can be mitigated by treatment with a tropomyosin receptor kinase B agonist

“…In vivo activation of TrkB by DHF administration has also been demonstrated in a number of experimental systems (Tzeng et al 2013, Zhang et al 2014). With 5 mg/kg/day DHF administration for 10 days (Fig.…”

“…This imbalance between excitatory and inhibitory neurotransmission has the potential to cause side effects, especially in DHF-treated, sham-irradiated controls. Finally, TrkB is expressed in various neuronal and glial populations and its activation has the potential to affect excitatory and inhibitory circuits, as well as neuroinflammation, in different brain regions (Huang and Reichardt 2003, Zhang et al 2003, Zhang et al 2014). A clear understanding of the effects of DHF on different cell populations will be crucial to designing effective treatments for various neurological disorders.…”

“…When administered systemically, DHF was shown to cross the blood-brain-barrier and specifically activated the TrkB receptor in the brain (Jang et al 2010), leading to long-lasting activation of BDNF signaling pathways (Liu et al 2014). Its therapeutic potential was demonstrated in rodent models in several areas of neurological defects, including promoting motor neuron survival in an amyotrophic lateral sclerosis model (Korkmaz et al 2014), preventing synaptic loss and cognitive defects in an Alzheimer disease model (Zhang et al 2014), inhibiting return of fear memory following extinction (Baker-Andresen et al 2013), and enhancing cognitive functions in aged rats (Zeng et al 2012). However, the therapeutic potential of DHF on the cognitive defects from cranial irradiation has yet to be investigated.…”

Inflammation and activity augment brain-derived neurotrophic factor peripheral release

“…BDNF release to the spinal cord has been extensively studied where BDNF acts on spinal neurons facilitates spinal cord plasticity and long-term potentiation (LTP)-like activities, and is believed to contribute to spinal “central sensitization” (Tonra et al, 1998, Lever et al, 2001, Luo et al, 2001, Ng et al, 2007, Ha et al, 2008). BDNF is also able to act on microglia and facilitates tumor necrosis factor-α (TNF-α) release (Zhang et al, 2014), and TNF-α-potentiated N-methyl-D-aspartate (NMDA) receptor activation (Xu et al, 2010). BDNF release along the distal (peripheral) axonal branch has not been characterized.…”