Activation of microglial cells triggers a release of brain-derived neurotrophic factor (BDNF) inducing their proliferation in an adenosine A2A receptor-dependent manner: A2A receptor blockade prevents BDNF release and proliferation of microglia

Abstract

BackgroundBrain-derived neurotrophic factor (BDNF) has been shown to control microglial responses in neuropathic pain. Since adenosine A2A receptors (A2ARs) control neuroinflammation, as well as the production and function of BDNF, we tested to see if A2AR controls the microglia-dependent secretion of BDNF and the proliferation of microglial cells, a crucial event in neuroinflammation.MethodsMurine N9 microglial cells were challenged with lipopolysaccharide (LPS, 100 ng/mL) in the absence or in the presence of the A2AR antagonist, SCH58261 (50 nM), as well as other modulators of A2AR signaling. The BDNF cellular content and secretion were quantified by Western blotting and ELISA, A2AR density was probed by Western blotting and immunocytochemistry and cell proliferation was assessed by BrdU incorporation. Additionally, the A2AR modulation of LPS-driven cell proliferation was also tested in primary cultures of mouse microglia.ResultsLPS induced time-dependent changes of the intra- and extracellular levels of BDNF and increased microglial proliferation. The maximal LPS-induced BDNF release was time-coincident with an LPS-induced increase of the A2AR density. Notably, removing endogenous extracellular adenosine or blocking A2AR prevented the LPS-mediated increase of both BDNF secretion and proliferation, as well as exogenous BDNF-induced proliferation.ConclusionsWe conclude that A2AR activation plays a mandatory role controlling the release of BDNF from activated microglia, as well as the autocrine/paracrine proliferative role of BDNF.

MicroRNA-Let-7a regulates the function of microglia in inflammation

“…The neurotrophic factor, BDNF, has been reported to prevent axonal and neuronal damage due to various pathological insults (Dougherty et al, 2000). BDNF is also involved in neuro-inflammation via several modulators (Gomes et al, 2013). BDNF in the CNS is supplied by immune cells and increased GP145-TrkB has been suggested as a candidate for mediating a neuroprotective role in multiple sclerosis (Stadelmann et al, 2002).…”

“…MiR-Let-7a may promote the expression of BDNF in microglia under inflammatory conditions. During inflammation, microglia undergo changes in cell proliferation and morphology, and consequently synthesize and secrete both pro-inflammatory and anti-inflammatory components (Gomes et al, 2013). The neurotrophic factor, BDNF, has been reported to prevent axonal and neuronal damage due to various pathological insults (Dougherty et al, 2000).…”

Depression as a Microglial Disease

“…The fact that microglial stimulators, such as LPS, promote microglial BDNF production (even in situations in which total brain BDNF is reduced) [196][197][198][199] may underlie our recent finding that microglial stimulators (e.g., LPS, M-CSF) produce antidepressive effects in mice with CUS-induced microglial decline [43]. methodology is not adequate for routine use and future studies should focus on diagnostic procedures that will allow identification of microglial status.…”

Antagonism of Adenosine A1or A2AReceptors Amplifies the Effects of MDMA on Glial Activation in the Mouse Brain: Relevance to Caffeine–MDMA Interactions

“…20 The adenosine system critically regulates the function of glial cells 22,23 ; however, the relative importance of each receptor subtype in modulating glial activation and neuroinflammatory processes is still controversial. [28][29][30][31][32] Both in vitro and in vivo studies have consistently indicated that the stimulation of either A 1 or A 2A receptors may attenuate neuroinflammation, as it promotes the synthesis of neurotrophic factors. [31][32][33][34] Therefore, counteraction of these effects might underlie the results observed in this study following the administration of adenosine receptor antagonists.…”