Transmigrating Neutrophils Shape the Mucosal Microenvironment through Localized Oxygen Depletion to Influence Resolution of Inflammation

Highlights

• Infiltrating PMNs consume sufficient O₂ to render adjacent colonic epithelia hypoxic

• Hypoxia reporter mice demonstrate PMN-dependent hypoxia in inflamed colitic lesions

• CGD mice do not incite mucosal hypoxia and develop severe nonresolving colitis

• Mucosal HIF stabilization ameliorates colitis severity in wild-type and CGD mice

Summary

Acute intestinal inflammation involves early accumulation of neutrophils (PMNs) followed by either resolution or progression to chronic inflammation. Based on recent evidence that mucosal metabolism influences disease outcomes, we hypothesized that transmigrating PMNs influence the transcriptional profile of the surrounding mucosa. Microarray studies revealed a cohort of hypoxia-responsive genes regulated by PMN-epithelial crosstalk. Transmigrating PMNs rapidly depleted microenvironmental O₂ sufficiently to stabilize intestinal epithelial cell hypoxia-inducible factor (HIF). By utilizing HIF reporter mice in an acute colitis model, we investigated the relative contribution of PMNs and the respiratory burst to “inflammatory hypoxia” in vivo. CGD mice, lacking a respiratory burst, developed accentuated colitis compared to control, with exaggerated PMN infiltration and diminished inflammatory hypoxia. Finally, pharmacological HIF stabilization within the mucosa protected CGD mice from severe colitis. In conclusion, transcriptional imprinting by infiltrating neutrophils modulates the host response to inflammation, via localized O₂ depletion, resulting in microenvironmental hypoxia and effective inflammatory resolution.