?7 Nicotinic Acetylcholine Receptor Signaling Modulates Ovine Fetal Brain Astrocytes Transcriptome in Response to Endotoxin.

ABSTRACT: Neuroinflammation in utero may result in lifelong neurological disabilities. Astrocytes play a pivotal role in this process, but the mechanisms are poorly understood. No early postnatal treatment strategies exist to enhance neuroprotective potential of astrocytes. We hypothesized that agonism on ?7 nicotinic acetylcholine receptor (?7nAChR) in fetal astrocytes will augment their neuroprotective transcriptome profile, while the inhibition 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 astrocytes cultures re-exposed to LPS in the presence of a selective ?7nAChR agonist or antagonist. Our RNAseq findings show that a pro-inflammatory astrocyte transcriptome phenotype acquired in vitro by LPS stimulation is reversed with ?7nAChR agonistic stimulation. Conversely, ?7nAChR inhibition potentiates the pro-inflammatory astrocytic transcriptome phenotype. Furthermore, we conducted a secondary transcriptome analysis against the identical ?7nAChR experiments in fetal sheep primary microglia cultures. Similar to findings in fetal microglia, in fetal astrocytes we observed a memory effect of in vivo exposure to inflammation, expressed in a perturbation of the iron homeostasis signaling pathway (hemoxygenase 1, HMOX1), which persisted under pre-treatment with ?7nAChR antagonist but was reversed with ?7nAChR agonist. For both glia cell types, common pathways activated due to LPS included neuroinflammation signaling and NF-?B signaling in some, but not all comparisons. However, overall, the overlap on the level of signaling pathways was rather minimal. Astrocytes, not microglia-the primary immune cells of the brain, were characterized by unique inhibition patterns of STAT3 pathway due to agonistic stimulation of ?7nAChR prior to LPS exposure. Lastly, we discuss the implications of our findings for fetal and postnatal brain development.

SUBMITTER: Cao M 

PROVIDER: S-EPMC6520997 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature