Indole-3-carbinol-dependent aryl hydrocarbon receptor signaling attenuates the inflammatory response in experimental necrotizing enterocolitis

Necrotizing enterocolitis (NEC) causes significant morbidity and mortality in premature infants; therefore, the identification of therapeutic and preventative strategies against NEC remains a high priority. The ligand-dependent transcription factor aryl hydrocarbon receptor (AhR) is well known to contribute to the regulation of intestinal microbial communities and amelioration of intestinal inflammation. However, the role of AhR signaling in NEC is unclear. Experimental NEC was induced in four-day-old wild-type mice or mice lacking AhR expression in the intestinal epithelial cells (AhR?rIEC) or in CD11c+ cells (AhR?rCD11c) by subjecting animals to twice daily hypoxic stress and gavage feeding with formula supplemented with lipopolysaccharide and enteric bacteria. During NEC, compared to wild-type mice treated with vehicle, littermates treated with an AhR pro-ligand, indole-3-carbinol (I3C), had reduced expression of Il1b and Marco, a scavenger receptor that mediates dendritic cell activation and the recognition and clearance of bacterial pathogens by macrophages. Furthermore, I3C treatment lead to the downregulation of genes involved in cytokine and chemokine as revealed by pathway enrichment analysis. AhR?rIEC and their cre-negative mouse littermates were similarly susceptible to experimental NEC, whereas AhR?rCD11c mice with NEC exhibited heightened inflammatory responses compared to their cre-negative mouse littermates. In seeking to determine the mechanisms involved in this increased inflammatory response, we identified the Tim-4- monocyte-dependent subset of macrophages as increased in AhR?rCD11c mice compared to their cre-negative littermates. Taken together, these findings demonstrate the potential for AhR ligands as a novel immunotherapeutic approach to the management of this devastating disease. Overall design: Study the effect of the pro-ligand for Indole-3-carbinol-dependent aryl hydrocarbon receptor on neonatal necrotizing enterocolitis in mice