SIGIRR Mutation in Human Necrotizing Enterocolitis (NEC) Disrupts STAT3-Dependent microRNA Expression in Neonatal...

Area of Science:

• Immunology
• Gastroenterology
• Genetics

Background:

• Single immunoglobulin interleukin-1-related receptor (SIGIRR) inhibits Toll-like receptor (TLR) signaling.
• A novel SIGIRR stop mutation (p.Y168X) was identified in an infant with severe necrotizing enterocolitis (NEC).

Purpose of the Study:

• Investigate mechanisms of SIGIRR mutations in neonatal gut TLR hyper-responsiveness.
• Determine how SIGIRR mutations disrupt postnatal intestinal adaptation.

Main Methods:

• Generated transgenic mice with the SIGIRR p.Y168X mutation using CRISPR/Cas9.
• Assessed inflammation, STAT3 phosphorylation, miRNA, and IRAK1 expression in mouse and human intestinal cells.
• Utilized Western blot, qRT-PCR, and luciferase assays to study SIGIRR-STAT3 signaling.

Main Results:

• Sigirr^Tg mice exhibited increased intestinal inflammation and NF-κB activation with decreased miR-146a/miR-155 expression.
• The p.Y168X mutation impaired SIGIRR-mediated STAT3-dependent miRNA expression.
• Decreased miR-146a led to increased IRAK1 expression, hindering gut adaptation.

Conclusions:

• Uncovered a novel SIGIRR-STAT3-miRNA-IRAK1 repression pathway regulating postnatal intestinal adaptation.
• SIGIRR mutations identified in NEC disrupt this pathway, causing loss of intestinal immune tolerance.
• Provides insights into genetic mutations in SIGIRR contributing to NEC pathogenesis.