Children’s Hospital of Pittsburgh researchers found that blocking signals from toll-like receptor 4 (TLR4), a key molecule that normally switches on the intestine’s immune response, may help reverse necrotizing enterocolitis (NEC), a leading cause of death in premature newborns.
TLRs are key players in the innate immune system. Protruding from enterocytes that form the innermost barrier-like layer of the small and large intestines, TLR4 receptors are primed to recognize pathogenic bacteria and sound the alarm.
The scientists found that the stresses of oxygen deprivation and bombardment by bacterial toxins, conditions that can occur in premature infants with underdeveloped lungs, stimulate too much production of TLR4 in mice. This eventually leads to cellular suicide. They also stop enterocytes from migrating to close wounds in the intestines.
These events, which do not occur in the TLR4-deficient mice, allow NEC to spread as the fragile lining of the gut gives way, releasing a flood of pathogens into the bloodstream.
The team discovered a way to switch off the molecular alarm in mice with NEC by interfering with the production of a focal adhesion kinase (FAK) that the researchers found associated with TLR4. By shutting down FAK with siRNA, the TLR4 siren was silenced. Under these conditions, the researchers watched enterocytes regain the ability to migrate.
The study was presented at the “American Society for Cell Biology 47th Annual Meeting.”