alpha 7 nicotinic acetylcholine receptor signaling modulates the inflammatory phenotype of fetal brain microglia: first evidence of interference by iron homeostasis

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

来源：Scientific Reports, 2017, 7(1): 10645.

DOI：10.1038/s41598-017-09439-z

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 alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) in fetal microglia will augment their neuroprotective transcriptome profile, while the antagonistic stimulation of alpha 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 alpha 7nAChR agonist or antagonist. Our RNAseq and protein level findings show that a proinflammatory microglial phenotype acquired in vitro by LPS stimulation is reversed with alpha 7nAChR agonistic stimulation. Conversely, antagonistic alpha 7nAChR stimulation potentiates the pro-inflammatory microglial phenotype. Surprisingly, under conditions of LPS double-hit an interference of a postulated alpha 7nAChR - ferroportin signaling pathway may impede this mechanism. These results suggest a therapeutic potential of alpha 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 alpha 7nAChR signaling in neurodevelopment.

• 出版日期2017-9-6
• 单位McGill