α7 nicotinic acetylcholine receptor signalling modulates the inflammatory and iron homeostasis in fetal brain microglia

Cortes, M.; Cao, M.; Liu, H. L.; Moore, C. S.; Durosier, L. D.; Burns, P.; Fecteau, G.; Desrochers, A.; Barreiro, L. B.; Antel, J.; Frasch, M. G.

doi:10.1101/097295

bioRxiv · 10.1101/097295

α7 nicotinic acetylcholine receptor signalling modulates the inflammatory and iron homeostasis in fetal brain microglia

Cortes, M.·Cao, M.·Liu, H. L.·Moore, C. S.·Durosier, L. D.·Burns, P.·Fecteau, G.·Desrochers, A.·Barreiro, L. B.·Antel, J.·Frasch, M. G.

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Abstract

Neuroinflammation in utero may result in life-long neurological disabilities. Microglia play a pivotal role, but the mechanisms are poorly understood. No early postnatal treatment strategies exist to enhance neuroprotective potential of microglia. We hypothesized that agonism on 7 nicotinic acetylcholine receptor (7nAChR) in fetal microglia will augment their neuroprotective transcriptome profile, while the antagonistic stimulation of 7nAChR will achieve the opposite. Using an in vivo - in vitro model of developmental programming of neuroinflammation induced by lipopolysaccharide (LPS), we validated this hypothesis in primary fetal sheep microglia cultures re-exposed to LPS in presence of a selective 7nAChR agonist or antagonist. Our RNAseq and protein level findings show that a pro-inflammatory microglial phenotype acquired in vitro by LPS stimulation is reversed with 7nAChR agonistic stimulation. Conversely, antagonistic 7nAChR stimulation potentiates the pro-inflammatory microglial phenotype. Surprisingly, under conditions of LPS double-hit an interference of a postulated 7nAChR - ferroportin signaling pathway may impede this mechanism. These results suggest a therapeutic potential of 7nAChR agonists in early re-programming of microglia in neonates exposed to in utero inflammation via an endogenous cerebral cholinergic anti-inflammatory pathway. Future studies will assess the role of interactions between inflammation-triggered microglial iron sequestering and 7nAChR signaling in neurodevelopment.

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Cortes, M., Cao, M., Liu, H. L., Moore, C. S., Durosier, L. D., Burns, P., Fecteau, G., Desrochers, A., Barreiro, L. B., Antel, J., Frasch, M. G.. 2017-01-02. α7 nicotinic acetylcholine receptor signalling modulates the inflammatory and iron homeostasis in fetal brain microglia. https://doi.org/10.1101/097295

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