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

Eric L Campbell1, Walter J Bruyninckx2, Caleb J Kelly1

  • 1Mucosal Inflammation Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.

Immunity
|January 14, 2014
PubMed

Insights

Infiltrating neutrophils cause localized oxygen depletion, creating hypoxia that helps resolve acute intestinal inflammation. Stabilizing this hypoxia protects against severe colitis.

Area of Science:

  • Gastroenterology
  • Immunology
  • Molecular Biology

Background:

  • Acute intestinal inflammation involves neutrophil infiltration, which can lead to chronic disease.
  • Mucosal metabolism significantly impacts inflammatory disease outcomes.
  • Neutrophil-epithelial interactions are crucial in modulating intestinal inflammation.

Purpose of the Study:

  • To investigate how transmigrating neutrophils influence the transcriptional profile of the intestinal mucosa.
  • To determine the role of neutrophil-derived "inflammatory hypoxia" in acute colitis.
  • To explore the therapeutic potential of modulating hypoxia in intestinal inflammation.

Main Methods:

  • Microarray analysis to identify hypoxia-responsive genes regulated by neutrophil-epithelial crosstalk.
  • Utilizing hypoxia-inducible factor (HIF) reporter mice in an acute colitis model.
  • Comparing colitis severity, neutrophil infiltration, and inflammatory hypoxia in wild-type and CGD (chronic granulomatous disease) mice.
  • Assessing the protective effects of pharmacological HIF stabilization in CGD mice.

Main Results:

  • Neutrophil transmigration led to rapid depletion of microenvironmental oxygen, stabilizing HIF in epithelial cells.
  • CGD mice, lacking a respiratory burst, exhibited exacerbated colitis with increased neutrophil infiltration and reduced inflammatory hypoxia.
  • Pharmacological stabilization of HIF in the mucosa conferred protection against severe colitis in CGD mice.

Conclusions:

  • Infiltrating neutrophils imprint transcriptional changes in the host mucosa through localized oxygen depletion.
  • This process results in microenvironmental hypoxia, which is critical for the effective resolution of acute intestinal inflammation.
  • Targeting HIF stabilization offers a potential therapeutic strategy for inflammatory bowel diseases.

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