In seeking to further understand the role of enterocyte TLR4 in the pathogenesis of intestinal inflammation, our laboratory recently has examined the role of enterocyte TLR4 activation in the pathogenesis of necrotizing enterocolitis (NEC) (32) . NEC is the leading cause of death from gastrointestinal disease in preterm infants (71) , and, currently, is one of the leading causes of death of newborns in the United States overall with a mortality rate of nearly 15% (82) . We have established recently that enterocyte TLR4 activation plays a critical role in the pathogenesis of NEC (32) . Specifically, we found that NEC in both mice and humans is associated with increased expression of TLR4 in the intestinal mucosa, and that physiological stressors associated with NEC development, namely exposure to LPS and hypoxia, sensitize the murine intestinal epithe-lium to LPS through upregulation of TLR4 (32) . In support of a critical role for TLR4 in the development of NEC, TLR4-mutant C3H/HeJ mice were protected from the development of NEC compared with wild-type C3H/HeOUJ littermates (32), a finding consistent with previous work by Caplan et al. (33) . TLR4 activation in vitro led to increased enterocyte injury by induction of enterocyte apoptosis and reduced epithelial healing, due to an inhibition of enterocyte migration and proliferation. This latter finding suggests a role for enterocyte TLR4 in the regulation of intestinal mucosal repair. In support of this possibility, increased NEC severity in wildtype C3H/HeOUJ mice resulted from increased enterocyte apoptosis and reduced enterocyte restitution and proliferation compared with TLR4-mutant mice. TLR4 signaling also led to increased serine-phosphorylation of intestinal focal adhesion kinase (FAK), a molecule necessary for efficient enterocyte migration. Surprisingly, TLR4 coimmunoprecipitated with FAK in enterocytes, and siRNA-mediated FAK inhibition restored enterocyte migration after TLR4 activation, demonstrating that the FAK-TLR4 association regulates intestinal healing. Taken together, these findings demonstrate a critical role for TLR4 signaling in the intestinal epithelium in the development of NEC through effects on enterocyte injury and repair (32) .