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Neutrophil‐epithelial interactions modulate the inflammatory microenvironment during colitis

Neutrophil (PMN) accumulation in crypt abscesses is a pathological hallmark of ulcerative colitis. We hypothesized that transmigrating neutrophils influence the transcriptional profile of intestinal epithelia. Microarray studies revealed a cohort of hypoxia‐responsive genes regulated by PMN‐epithelial crosstalk. Transmigrating PMNs rapidly depleted microenvironmental O2 sufficiently to stabilize epithelial hypoxia‐inducible factor (HIF). Utilizing HIF reporter mice in a TNBS colitis model, we investigated the contribution of PMNs and the oxidative burst to “inflammatory hypoxia”. Gp91phox−/− mice, lacking functional NADPH oxidase, developed exacerbated colitis with enhanced PMN infiltration and diminished inflammatory hypoxia. Pharmacological intervention with a HIF‐stabilizing compound resulted in restoration of mucosal HIF‐signaling concomitant with abrogation of colitis‐severity in the gp91phox−/− mice. In conclusion, transcriptional imprinting of host tissue by infiltrating PMNs modulates host responses to inflammation. Likewise, the oxidative burst contributes fundamentally to localized O2 depletion, resultant microenvironmental hypoxia and effective inflammatory resolution. Funding: CCFA and NIH.