TY - JOUR T1 - α7 nicotinic acetylcholine receptor signaling modulates the inflammatory and iron homeostasis in fetal brain microglia JF - bioRxiv DO - 10.1101/097295 SP - 097295 AU - M. Cortes AU - M. Cao AU - H.L. Liu AU - C.S Moore AU - L.D. Durosier AU - P. Burns AU - G. Fecteau AU - A. Desrochers AU - L.B. Barreiro AU - J.P. Antel AU - M.G. Frasch Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/01/02/097295.abstract N2 - Neuroinflammation in utero may result in life-long neurological disabilities. Microglia play a pivotal role in this process, but the mechanisms are still being established. No early postnatal treatment strategies exist to enhance neuroprotective potential of microglia. We hypothesized that agonism on α7 nicotinic acetylcholine receptor (α7nAChR) in fetal microglia will augment their neuroprotective transcriptome profile, while the antagonistic stimulation of α7nAChR 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 α7nAChR agonist or antagonist. Our findings suggest that a pro-inflammatory microglial phenotype acquired in vitro by LPS stimulation is reversed with α7nAChR agonistic stimulation. Conversely, antagonistic α7nAChR stimulation potentiates the pro-inflammatory microglial phenotype. Surprisingly, under conditions of LPS double-hit an interference of a postulated α7nAChR - ferroportin signaling pathway may impede this mechanism. These results suggest a therapeutic potential of α7nAChR agonists in early treatment or re-programming of microglia in neonates exposed to in utero inflammation via an endogenous cerebral cholinergic anti-inflammatory pathway. Our findings further point to the significance of microglial iron homeostasis in double-hit LPS scenarios. Interactions between inflammation-triggered microglial iron sequestering and α7nAChR stimulation require further studies to assess the full therapeutic potential of this novel brain signaling network and its role in neurodevelopment and programming of cognitive dysfunction in adult life. ER -