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

被引：429

作者：

Campbell, Eric L. ^{[1
]}

Bruyninckx, Walter J. ^{[2
]}

Kelly, Caleb J. ^{[1
]}

Glover, Louise E. ^{[1
]}

McNamee, Eoin N. ^{[1
]}

Bowers, Brittelle E. ^{[1
]}

Bayless, Amanda J. ^{[1
]}

Scully, Melanie ^{[1
]}

Saeedi, Bejan J. ^{[1
]}

Golden-Mason, Lucy ^{[3
]}

Ehrentraut, Stefan F. ^{[1
]}

Curtis, Valerie F. ^{[1
]}

Burgess, Adrianne ^{[1
]}

Garvey, John F. ^{[4
]}

Sorensen, Amber ^{[3
]}

Nemenoff, Raphael ^{[3
]}

Jedlicka, Paul ^{[3
]}

Taylor, Cormac T. ^{[4
]}

Kominsky, Douglas J. ^{[1
]}

Colgan, Sean P. ^{[1
]}

机构：

[1] Univ Colorado, Mucosal Inflammat Program, Aurora, CO 80045 USA

[2] Hanover Coll, Dept Biol, Hanover, IN 47243 USA

[3] Univ Colorado, Aurora, CO 80045 USA

[4] Natl Univ Ireland Univ Coll Dublin, Dublin 4, Ireland

来源：

IMMUNITY | 2014年 / 40卷 / 01期

关键词：

CHRONIC GRANULOMATOUS-DISEASE; INTESTINAL TREFOIL FACTOR; INDUCIBLE FACTOR-I; EXPERIMENTAL COLITIS; BARRIER FUNCTION; BOWEL-DISEASE; NADPH OXIDASE; HYPOXIA; MACROPHAGES; SUPEROXIDE;

D O I：

10.1016/j.immuni.2013.11.020

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

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 O-2 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 O-2 depletion, resulting in microenvironmental hypoxia and effective inflammatory resolution.

引用

页码：66 / 77

页数：12

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