Single Immunoglobulin Interleukin1-Related Receptor-TWIST1 Axis Regulates Barrier Function in Neonatal Intestine

Area of Science:

• Neonatal immunology
• Gastrointestinal biology
• Genetic disease mechanisms

Background:

• The genetic underpinnings of impaired intestinal barrier function in preterm infants, particularly in necrotizing enterocolitis (NEC), remain unclear.
• Single immunoglobulin interleukin-1-related receptor (SIGIRR) variants are linked to NEC, suggesting a role in regulating Toll-Like Receptor (TLR) signaling and gut integrity.

Purpose of the Study:

• To investigate how SIGIRR genetic variants disrupt neonatal intestinal barrier integrity.
• To determine the role of SIGIRR in promoting susceptibility to Gram-negative bacteria implicated in sepsis and NEC.

Main Methods:

• Utilized transgenic mice and preterm infant-derived enteroids expressing specific SIGIRR variants.
• Assessed epithelial junctional protein assembly and gut barrier function using an E. coli strain from neonatal sepsis.

Main Results:

• SIGIRR p.Y168X mutation in mice led to loss of junctional proteins, impaired barrier function, and exaggerated TLR signaling via TWIST1 activation.
• Mutant mice showed high susceptibility to E. coli bacteremia; TWIST1 inhibition or TLR4 deletion restored barrier integrity.
• Human enteroids with SIGIRR variants recapitulated barrier defects and TWIST1 activation, which were reversed by TWIST1 inhibition.

Conclusions:

• SIGIRR is crucial for maintaining neonatal intestinal epithelial barrier integrity by suppressing TWIST1-mediated disruption.
• Loss of SIGIRR function compromises the epithelial barrier, promoting bacterial translocation and contributing to NEC and neonatal sepsis pathogenesis.