Transcriptome Analysis Reveals Dynamic Microglial-Induced A1 Astrocyte Reactivity via C3/C3aR/NF-κB Signaling After...

Area of Science:

• Neuroscience
• Immunology
• Pathophysiology

Background:

• Microglia and astrocytes are central to neuroinflammation and ischemic stroke.
• A1 astrocytes, a neurotoxic subtype, are implicated in neurodegeneration but their role in ischemic stroke remains unclear.

Purpose of the Study:

• To investigate the role of A1 astrocytes in ischemic stroke pathophysiology.
• To identify molecular mechanisms driving A1 astrocyte formation and their therapeutic potential.

Main Methods:

• RNA sequencing (RNA-seq)
• Molecular and immunological techniques
• Behavioral tests
• Inhibition of A1 astrocyte induction

Main Results:

• Astrocyte phenotype shifts from beneficial A2 in the acute phase to detrimental A1 in the chronic phase post-ischemic stroke.
• Activated microglia (IL1α, TNF, C1q) induce A1 astrocytes.
• Inhibition of A1 astrocyte induction reduces reactive gliosis and improves stroke outcomes.
• Crosstalk between astrocytic C3 and microglial C3aR, along with NF-κB activation, drives A1 astrocyte formation.

Conclusions:

• A2 astrocytes dominate the acute phase, while A1 astrocytes are enriched in the chronic phase of ischemic stroke.
• The C3/C3aR/NF-κB signaling pathway is crucial for A1 astrocyte induction.
• Targeting the C3/C3aR/NF-κB pathway represents a novel therapeutic strategy for ischemic stroke.