Chronic complement dysregulation drives neuroinflammation after traumatic brain injury: a transcriptomic study.

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• The complement system drives neuroinflammation and brain damage after traumatic brain injury (TBI).
• Characterizing complement gene expression and its therapeutic inhibition in the injured brain is crucial.
• Previous studies assessed limited outcomes, necessitating a comprehensive analysis of complement's role post-TBI.

Purpose of the Study:

• To comprehensively analyze complement gene expression profiles alongside neuroinflammatory pathways after TBI.
• To assess the therapeutic effects of complement inhibition on neuroinflammation and neuropathology post-TBI.
• To investigate complement gene expression in the normal and aging brain.

Main Methods:

• Utilized high-throughput NanoString gene expression technology to analyze 59 complement genes and neuroinflammatory markers.
• Studied gene expression at multiple time points (days 3, 7, 28, and 1-2 years) post-TBI in a mouse model.
• Assessed the impact of the complement inhibitor CR2-Crry on TBI-induced transcriptomic changes.

Main Results:

• TBI upregulated astrogliosis, immune cell activation, and cellular stress markers, while downregulating neuronal and synaptic markers.
• Complement gene expression was broadly upregulated post-TBI, with sustained C2, C3, and C4 expression even 2 years later.
• CR2-Crry treatment significantly ameliorated TBI-induced transcriptomic changes, though some immune and synaptic genes remained dysregulated.

Conclusions:

• The complement system is broadly and chronically dysregulated after TBI, highlighting its therapeutic potential.
• Complement inhibition is a promising strategy for TBI, but may require combination therapy for optimal neuroprotection.
• Further research into complement gene expression in normal and aging brains is warranted.