IKKβ deletion in intestinal macrophages but not intestinal epithelial cells ameliorates intestinal injury in a neonatal mouse NEC model (902.7)

Abstract

Necrotizing enterocolitis (NEC) is thought to be due to an exaggerated inflammatory response in the premature intestine. We previously found that nuclear factor‐κB (NF‐κB) mediates the intestinal injury in experimental NEC. However, the cell‐types in which NF‐κB activation is critical are unknown. Here, we examine the respective role of epithelial cell and macrophage NF‐κB activation in a neonatal mouse NEC model, using mice lacking IKKβ, the upstream kinase responsible for NF‐κB activation in these cell‐types. Lys‐Cre+/‐ IKKβF/F, Villin‐Cre+/‐ IKKβF/F and IKKβF/F mice were exposed to a NEC protocol consisting in adult commensal bacteria inoculation/ hypoxia/cold stress/formula feeding. Pups were closely observed and euthanized at 72 hours of age or when showing signs of distress and their intestine examined histologically. Cell‐specific deletion of IKKβ was confirmed in the neonatal pups. The incidence of severe NEC (score 蠅2) was significantly decreased in Lys‐Cre+/‐ IKKβF/F pups compared to IKK βF/F controls (3/23 vs 16/23, χ2=12.9, p<0.001). However, there were no difference in the incidence of severe NEC between Villin‐Cre+/‐ IKKβF/F and IKK βF/F controls (13/28 vs 19/34, χ2=0.23, NS). Our data suggest that NF‐κB in macrophages but not intestinal epithelial cells mediates the intestinal injury in our mouse model of NEC.Grant Funding Source: NIH (R01‐HD060876)