Adenosine A2B receptor-mediated leukemia inhibitory factor release from astrocytes protects cortical neurons against excitotoxicity

Abstract

BackgroundNeuroprotective and neurotrophic properties of leukemia inhibitory factor (LIF) have been widely reported. In the central nervous system (CNS), astrocytes are the major source for LIF, expression of which is enhanced following disturbances leading to neuronal damage. How astrocytic LIF expression is regulated, however, has remained an unanswered question. Since neuronal stress is associated with production of extracellular adenosine, we investigated whether LIF expression in astrocytes was mediated through adenosine receptor signaling.MethodsMouse cortical neuronal and astrocyte cultures from wild-type and adenosine A2B receptor knock-out animals, as well as adenosine receptor agonists/antagonists and various enzymatic inhibitors, were used to study LIF expression and release in astrocytes. When needed, a one-way analysis of variance (ANOVA) followed by Bonferroni post-hoc test was used for statistical analysis.ResultsWe show here that glutamate-stressed cortical neurons induce LIF expression through activation of adenosine A2B receptor subtype in cultured astrocytes and require signaling of protein kinase C (PKC), mitogen-activated protein kinases (MAPKs: p38 and ERK1/2), and the nuclear transcription factor (NF)-κB. Moreover, LIF concentration in the supernatant in response to 5′-N-ethylcarboxamide (NECA) stimulation was directly correlated to de novo protein synthesis, suggesting that LIF release did not occur through a regulated release pathway. Immunocytochemistry experiments show that LIF-containing vesicles co-localize with clathrin and Rab11, but not with pHogrin, Chromogranin (Cg)A and CgB, suggesting that LIF might be secreted through recycling endosomes. We further show that pre-treatment with supernatants from NECA-treated astrocytes increased survival of cultured cortical neurons against glutamate, which was absent when the supernatants were pre-treated with an anti-LIF neutralizing antibody.ConclusionsAdenosine from glutamate-stressed neurons induces rapid LIF release in astrocytes. This rapid release of LIF promotes the survival of cortical neurons against excitotoxicity.

Adenosine A2B receptor activation stimulates glucose uptake in the mouse forebrain

“…Such mechanism would be essential to avoid an hypoenergetic crisis, which might lead to cell death. Indeed, A 2B R activation has been linked with increased survival of hippocampal and cortical cells under oxygen-glucose deprivation [30][31][32]. Hence, A 2B Rs seem to generally assist the homeostasis of brain cells in a manner similar to that occurring in the periphery.…”

“…Although normally metabolic boosters (nootropics) do not mitigate the outcome of neurodegenerative disorders, A 2B R agonists eventually possess multiple beneficial actions including boosting cerebral glucose metabolism and increasing cell survival apart from effects on energy metabolism [30][31][32]. Therefore, further studies are invited to evaluate the clinical potential of A 2B R agonists in both animals and man.…”

Mechanisms of heterosynaptic metaplasticity

“…HFS and activation of A2BRs can trigger the release of cytokines from astrocytes [84,85], and this has been proposed as a metaplastic mechanism for inhibiting LTP both homo-and heterosynaptically [86], and indeed, we have recently shown that A2BR activation can generate a cell-wide inhibition of LTP [40]. It is therefore possible that priming stimulation in stratum oriens modulates plasticity in stratum radiatum by eliciting widespread cytokine release from astrocytes, a hypothesis we consider worthy of future investigation.…”

Targeting of Tumor Necrosis Factor Alpha Receptors as a Therapeutic Strategy for Neurodegenerative Disorders

“…LIF is a neurotrophic cytokine, which, in the brain, is mainly produced by astrocytes. Elevated levels of LIF were shown to promote the maturation of oligodendrocytes [208], and LIF was found to protect primary neurons against excitotoxicity [209]. Moreover, in the EAE mouse model LIF was demonstrated to protect axons in the brain from acute inflammatory damage [210].…”