Long non-coding RNA ANRIL/p65 negative feedback loop protects intestinal barrier function in inflammatory bowel...

Area of Science:

• Gastroenterology
• Molecular Biology
• Immunology

Background:

• Inflammatory bowel disease (IBD) is characterized by compromised intestinal barrier function.
• Long non-coding RNAs (lncRNAs) are implicated in IBD pathogenesis, potentially affecting barrier integrity.
• The specific role of the lncRNA ANRIL in IBD-related barrier dysfunction remains largely unexplored.

Purpose of the Study:

• To investigate the role of the downregulated lncRNA ANRIL in modulating intestinal barrier function in IBD.
• To elucidate the underlying molecular mechanisms by which ANRIL influences intestinal barrier integrity.
• To explore the therapeutic potential of ANRIL in IBD models.

Main Methods:

• Analysis of ANRIL expression in IBD patients and correlation with disease severity.
• Overexpression of ANRIL in dextran sulfate sodium (DSS)-induced mouse colitis models.
• Transcriptome sequencing to identify pathways affected by ANRIL.
• Investigation of the ANRIL/NF-κB signaling axis using cell and animal models.
• Assessment of ANRIL's interaction with YY1 and p65.

Main Results:

• ANRIL expression is significantly downregulated in ulcerative colitis (UC) patients, correlating with disease progression.
• ANRIL overexpression in DSS-induced colitis mice reduced colonic damage, suppressed pro-inflammatory cytokines (IL-6, TNF-α, IL-1β), and improved intestinal barrier function.
• ANRIL overexpression suppressed NF-κB pathway activation in both mouse colitis and LPS-induced cell models.
• ANRIL competitively binds YY1, inhibiting YY1-p65 interaction and subsequent NF-κB transcriptional activity.
• A negative feedback loop was identified where p65 binds the ANRIL promoter, enhancing ANRIL expression.

Conclusions:

• The lncRNA ANRIL plays a protective role in maintaining intestinal barrier function in IBD.
• ANRIL ameliorates inflammation and barrier defects by inhibiting the NF-κB signaling pathway via interaction with YY1 and p65.
• The ANRIL/p65 negative feedback loop presents a promising therapeutic target for IBD treatment.