Silencing PAR-2 in macrophages promotes PANoptosis and triggers duodenal microinflammation in functional dyspepsia

Area of Science:

• Immunology
• Gastroenterology
• Cell Biology

Background:

• Macrophage PANoptosis is increasingly recognized for its role in immune system regulation and inflammatory diseases.
• Functional dyspepsia (FD) involves complex immune dysregulation potentially linked to macrophage activity and gastrointestinal dysfunction.

Purpose of the Study:

• To identify key genes involved in macrophage PANoptosis and their causal relationship with functional dyspepsia (FD).
• To elucidate the role of these genes and associated pathways in duodenal micro-inflammation in FD.
• To explore the NF-κB-PAR-2 axis as a potential therapeutic target for FD.

Main Methods:

• Weighted gene co-expression network analysis (WGCNA) and Mendelian randomization were used to identify key genes.
• Gene set enrichment analysis (GSEA) explored gene functions and pathways.
• In vivo and in vitro experiments assessed macrophage PANoptosis and duodenal micro-inflammation in FD models.

Main Results:

• 489 target genes were identified, with ARL5B, CAPN3, CDK5RAP3, and F2RL1 showing a causal link to FD.
• Key genes, especially PAR-2, are involved in NF-κB, AMPK, and Toll-like receptor signaling pathways.
• Silencing PAR-2 in macrophages exacerbated PANoptosis and induced duodenal micro-inflammation in FD.

Conclusions:

• The NF-κB-PAR-2 axis is a central regulatory mechanism in macrophage-mediated duodenal micro-inflammation in FD.
• Targeting macrophage PANoptosis and the NF-κB-PAR-2 axis presents potential therapeutic avenues for FD.
• This study provides novel insights into the pathogenesis of FD and identifies potential diagnostic and therapeutic targets.