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Neutrophil-derived reactive oxygen orchestrates epithelial cell signaling events during intestinal repair.

J. Matthews,Joshua A. Owens,C. Naudin,B. Saeedi,Ashfaqul Alam,April R. Reedy,B. Hinrichs,R. Sumagin,A. Neish,Rheinallt M. Jones

Published 2019 in American Journal of Pathology

ABSTRACT

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 Nox2 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 redox protein signaling in the epithelium. To simulate epithelial exposure to high levels of reactive oxygen produced by neutrophils and gain new insight into this redox signaling, epithelial cells were treated with H2O2 and biochemical experiments conducted and a proteome-wide screen performed using isotope-coded affinity tags to detect proteins oxidized following 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 Rac1 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.

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