Neutrophil-Derived Reactive Oxygen Orchestrates Epithelial Cell Signaling Events during Intestinal Repair

Jason D. Matthews, Joshua A. Owens, Crystal R. Naudin, Bejan J. Saeedi, Ashfaqul Alam, April R. Reedy, Benjamin H. Hinrichs, Ronen Sumagin, Andrew S. Neish, Rheinallt M. Jones

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Recent evidence has demonstrated that reactive oxygen (eg, hydrogen peroxide) can activate host cell signaling pathways that function in repair. We show that mice deficient in their capacity to generate reactive oxygen by the NADPH oxidase 2 holoenzyme, an enzyme complex highly expressed in neutrophils and macrophages, have disrupted capacity to orchestrate signaling events that function in mucosal repair. Similar observations were made for mice after neutrophil depletion, pinpointing this cell type as the source of the reactive oxygen driving oxidation-reduction protein signaling in the epithelium. To simulate epithelial exposure to high levels of reactive oxygen produced by neutrophils and gain new insight into this oxidation-reduction signaling, epithelial cells were treated with hydrogen peroxide, biochemical experiments were conducted, and a proteome-wide screen was performed using isotope-coded affinity tags to detect proteins oxidized after exposure. This analysis implicated signaling pathways regulating focal adhesions, cell junctions, and maintenance of the cytoskeleton. These pathways are also known to act via coordinated phosphorylation events within proteins that constitute the focal adhesion complex, including focal adhesion kinase and Crk-associated substrate. We identified the Rho family small GTP–binding protein Ras-related C3 botulinum toxin substrate 1 and p21 activated kinases 2 as operational in these signaling and localization pathways. These data support the hypothesis that reactive oxygen species from neutrophils can orchestrate epithelial cell–signaling events functioning in intestinal repair.

Original languageEnglish
Pages (from-to)2221-2232
Number of pages12
JournalAmerican Journal of Pathology
Issue number11
StatePublished - Nov 2019

Bibliographical note

Publisher Copyright:
© 2019 American Society for Investigative Pathology

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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