α7 Nicotinic Acetylcholine Receptor Signaling Modulates Ovine Fetal Brain Astrocytes Transcriptome in Response to...

Area of Science:

• Neuroscience
• Developmental Biology
• Immunology

Background:

• In utero neuroinflammation can lead to lifelong neurological deficits.
• Astrocytes are key players in neuroinflammation, but mechanisms are unclear.
• No current postnatal treatments enhance astrocyte neuroprotection.

Purpose of the Study:

• To investigate the role of alpha7 nicotinic acetylcholine receptor (α7nAChR) agonism/antagonism in fetal astrocytes.
• To determine if α7nAChR modulation can alter the astrocyte transcriptome in response to inflammation.
• To explore potential therapeutic strategies for preventing neuroinflammation-induced disabilities.

Main Methods:

• Utilized an in vivo-in vitro model of developmental neuroinflammation using lipopolysaccharide (LPS) in fetal sheep.
• Primary fetal sheep astrocytes were stimulated with LPS in the presence of selective α7nAChR agonists or antagonists.
• RNA sequencing (RNAseq) was performed to analyze transcriptome profiles and signaling pathways.

Main Results:

• α7nAChR agonism reversed the pro-inflammatory astrocyte transcriptome induced by LPS.
• α7nAChR inhibition potentiated the pro-inflammatory astrocyte phenotype.
• A persistent memory effect on iron homeostasis (HMOX1) was observed in astrocytes, reversed by α7nAChR agonist.

Conclusions:

• Modulating α7nAChR in fetal astrocytes can significantly alter their response to inflammatory stimuli.
• α7nAChR agonism demonstrates neuroprotective potential by reversing inflammatory gene expression.
• Findings suggest α7nAChR as a potential therapeutic target for mitigating fetal neuroinflammation.