Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation

Immunity. 2014 Jan 16;40(1):66-77. doi: 10.1016/j.immuni.2013.11.020. Epub 2014 Jan 9.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Communication
  • Cell Movement
  • Cells, Cultured
  • Cellular Microenvironment
  • Colitis / chemically induced
  • Colitis / immunology*
  • Colon / pathology
  • Disease Models, Animal
  • Hypoxia / chemically induced
  • Hypoxia / immunology*
  • Hypoxia-Inducible Factor 1 / metabolism
  • Membrane Glycoproteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microarray Analysis
  • Mucous Membrane / metabolism*
  • Mucous Membrane / pathology
  • NADPH Oxidase 2
  • NADPH Oxidases / genetics
  • Neutrophils / pathology*
  • Oxidative Stress
  • Oxygen / metabolism
  • Protein Stability / drug effects
  • Transendothelial and Transepithelial Migration


  • Hypoxia-Inducible Factor 1
  • Membrane Glycoproteins
  • Cybb protein, mouse
  • NADPH Oxidase 2
  • NADPH Oxidases
  • Oxygen