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J Immunol. 2018 Jun 15;200(12):3950-3961. doi: 10.4049/jimmunol.1701643. Epub 2018 Apr 30.

REDD1/Autophagy Pathway Is Associated with Neutrophil-Driven IL-1β Inflammatory Response in Active Ulcerative Colitis.

Author information

1
Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis 68100, Greece.
2
Department of Pathology, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis 68100, Greece.
3
First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis 68100, Greece.
4
Gastrointestinal Endoscopy Unit, University Hospital of Alexandroupolis, Democritus University of Thrace, Alexandroupolis 68100, Greece; and.
5
Department of Clinical Pathobiochemistry, Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technical University of Dresden, 01307 Dresden, Germany.
6
Laboratory of Molecular Hematology, Democritus University of Thrace, Alexandroupolis 68100, Greece; kritis@med.duth.gr pskendro@med.duth.gr.

Abstract

Infiltration of neutrophils into colonic mucosa has been associated with the severity of ulcerative colitis (UC). We investigated the effect of disease microenvironment on the release of neutrophil extracellular traps (NETs) as well as the involved mechanisms in NETosis and whether certain NET proteins are correlated with disease phenotype. Peripheral blood neutrophils, sera, and colonic tissue were collected from treatment-naive and mesalazine-treated patients with active UC, treatment-naive patients with active Crohn's disease, patients suffering from infectious colitis, or healthy individuals (controls). Analysis of colonic biopsy specimens and peripheral blood neutrophils for the presence of NET-related markers using immunofluorescence confocal microscopy, ELISA, immunoblotting, flow cytometry, and quantitative PCR were performed. In vitro cell and tissue culture systems were further deployed. The local inflammatory response in colon in UC, but not Crohn's disease, is characterized by the presence of NETs carrying bioactive IL-1β and thrombogenic tissue factor. The inflammatory environment of UC is able to induce neutrophil activation, IL-1β expression, and NET release, as shown both ex vivo and in vitro. REDD1 expression, as a mediator linking inflammation, autophagy, and NET release, was also specifically associated with the inflammatory response of UC. We show that neutrophil expression of REDD1 in colon tissue and the presence of IL-1β in neutrophils/NETs provide candidate biomarkers for the differential diagnosis of inflammatory colitis and possible targets for the treatment of UC, suggesting that UC shares common features with autoinflammatory disorders.

PMID:
29712770
DOI:
10.4049/jimmunol.1701643
[Indexed for MEDLINE]
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