title: Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation.
abstract: 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.
authors.affiliation: Mucosal Inflammation Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA. Electronic address: eric.campbell@ucdenver.edu.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Campbell
authors.affiliation: Department of Biology, Hanover College, Hanover, IN 47243, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Bruyninckx
authors.affiliation: Mucosal Inflammation Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Caleb J
authors.initials: CJ
authors.lastname: Kelly
authors.affiliation: Mucosal Inflammation Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Louise E
authors.initials: LE
authors.lastname: Glover
authors.affiliation: Mucosal Inflammation Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Eóin N
authors.initials: EN
authors.lastname: McNamee
authors.affiliation: Mucosal Inflammation Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Brittelle E
authors.initials: BE
authors.lastname: Bowers
authors.affiliation: Mucosal Inflammation Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Bayless
authors.affiliation: Mucosal Inflammation Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Scully
authors.affiliation: Mucosal Inflammation Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Bejan J
authors.initials: BJ
authors.lastname: Saeedi
authors.affiliation: University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Lucy
authors.initials: L
authors.lastname: Golden-Mason
authors.affiliation: Mucosal Inflammation Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Stefan F
authors.initials: SF
authors.lastname: Ehrentraut
authors.affiliation: Mucosal Inflammation Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Valerie F
authors.initials: VF
authors.lastname: Curtis
authors.affiliation: Mucosal Inflammation Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Adrianne
authors.initials: A
authors.lastname: Burgess
authors.affiliation: University College Dublin, Dublin 4, Ireland.
authors.forename: John F
authors.initials: JF
authors.lastname: Garvey
authors.affiliation: University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Amber
authors.initials: A
authors.lastname: Sorensen
authors.affiliation: University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Nemenoff
authors.affiliation: University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Jedlicka
authors.affiliation: University College Dublin, Dublin 4, Ireland.
authors.forename: Cormac T
authors.initials: CT
authors.lastname: Taylor
authors.affiliation: Mucosal Inflammation Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Kominsky
authors.affiliation: Mucosal Inflammation Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Colgan
mesh_terms: D000818:Animals; D002450:Cell Communication; D002465:Cell Movement; D002478:Cells, Cultured; D060833:Cellular Microenvironment; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D003106:Colon / Q000473:pathology; D004195:Disease Models, Animal; D000860:Hypoxia / Q000139:chemically induced / Q000276:immunology*; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D009092:Mucous Membrane / Q000378:metabolism* / Q000473:pathology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics; D009504:Neutrophils / Q000473:pathology*; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D057705:Transendothelial and Transepithelial Migration
chemical_list: D051793:Hypoxia-Inducible Factor 1; D008562:Membrane Glycoproteins; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D010100:Oxygen