Context-enriched interactome powered by proteomics helps the identification of novel regulators of macrophage...

Area of Science:

• Immunology
• Cardiovascular Biology
• Systems Biology

Background:

• Pro-inflammatory macrophage activation is crucial in cardiovascular disease (CVD) pathogenesis.
• Existing protein interactomes lack cell-type and disease-specific context, limiting their utility.
• Network approaches are valuable for understanding complex diseases like CVD.

Purpose of the Study:

• To develop context-specific protein networks for activated macrophages.
• To identify novel regulators of pro-inflammatory macrophage activation.
• To improve prediction of disease-relevant molecular players in CVD.

Main Methods:

• Integrated general interactome data with co-abundance networks from macrophage proteomics.
• Applied network proximity-based prioritization to identify candidate regulators.
• Validated candidate drivers using transcriptomics, proteomics, and in vitro loss-of-function experiments.

Main Results:

• Context-specific networks significantly improved the prediction of macrophage activation regulators.
• Prioritized candidates were enriched for inflammation, immunity, and CVD signatures.
• Identified and validated key protein drivers of pro-inflammatory signaling in macrophages.

Conclusions:

• Combining interactomes with cell-specific co-abundance networks enhances biological discovery.
• This approach successfully identified novel regulators of macrophage activation relevant to CVD.
• The findings provide a foundation for targeted therapeutic strategies against inflammation in cardiovascular disease.