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

ABSTRACT: 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 (AhRΔrIEC) or in CD11c+ cells (AhRΔrCD11c) 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. AhRΔrIEC and their cre-negative mouse littermates were similarly susceptible to experimental NEC, whereas AhRΔrCD11c 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 AhRΔrCD11c 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE154617 | GEO | 2021/03/03

REPOSITORIES: GEO

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Project description:The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates a broad range of target genes involved in the xenobiotic response, cell cycle control and circadian rhythm. AhR is constitutively expressed in macrophages, acting as key regulator of cytokine production. While proinflammatory cytokines, i.e., IL-1β, IL-6, IL-12, are suppressed through AhR activation, anti-inflammatory IL-10 is induced. However, the underlying mechanisms of those effects and the importance of the specific ligand structure are not yet completely understood. Therefore, we have compared the global gene expression pattern in activated murine bone marrow-derived macrophages (BMMs) subsequently to exposure with either benzo[a]pyrene (BaP) or indole-3-carbinol (I3C), representing xenobiotic vs. nutritional AhR ligands, respectively, by means of mRNA sequencing. AhR dependency of observed effects was proved using BMMs from AhR-knockout mice. In total, more than 1,000 differentially expressed genes (DEGs) could be mapped, covering a plethora of AhR-modulated effects on basal cellular processes, i.e., transcription and translation, but also immune functions, i.e., antigen presentation, cytokine production, and phagocytosis. Among DEGs were genes that are already known to be regulated by AhR, i.e., Irf1, Ido2, and Cd84. However, we identified DEGs not yet described to be AhR-regulated in macrophages so far, i.e., Slpi, Il12rb1, and Il21r. All six genes likely contribute to shifting the macrophage phenotype from proinflammatory to anti-inflammatory. The majority of DEGs were specific for BaP but not affected through I3C exposure, probably due to higher AhR affinity of BaP in comparison to I3C. Mapping of known aryl hydrocarbon response element (AHRE) sequence motifs in identified DEGs revealed more than 200 genes not possessing any AHRE, and therefore being not eligible for canonical regulation. Bioinformatic approaches modeled a central role of type I and type II interferons in the regulation of those genes. Additionally, RT-qPCR and ELISA confirmed a BaP- and AhR-dependent expressional induction and AhR-dependent secretion of IFN-γ, suggesting a potentially novel auto- or paracrine activation pathway of macrophages.

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

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