Editors' ChoiceCell Biology

First Damaging, Then Repairing

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Science Signaling  27 Sep 2011:
Vol. 4, Issue 192, pp. ec266
DOI: 10.1126/scisignal.4192ec266

Conditions such as inflammatory lung disease trigger infiltration of neutrophils across the lung epithelium, which damages the epithelial sheet. After acute injury, the epithelium is repaired through re-epithelialization, a process involving proliferation of the epithelial cells and restoration of its barrier function. Zemans et al. showed that neutrophil transmigration across monolayers of cells of a cultured lung epithelial cell line (Calu-3 cells) or primary human alveolar type II cells (ATII) caused wounds in the epithelium, disrupting the barrier function, which subsequently resolved over the following 48 to 72 hours through re-epithelialization. Transcriptional microarray analysis of the epithelial cells 90 minutes after transmigration by neutrophils revealed that expression of genes associated with the transcriptional regulatory activity of β-catenin increased, and this was confirmed at the protein level by immunostaining, which showed increased abundance of the transcription factor c-Myc and WISP1 (Wnt-inducible secreted protein 1) in cells near sites of transmigration. In unstimulated epithelial cells, β-catenin is associated with cellular adhesion sites, but after neutrophil transmigration less β-catenin was detected at the cell junctions and instead was detected in the nuclei of the epithelial cells. Activation of a β-catenin reporter gene confirmed the transcriptional activity of β-catenin. Neutrophil transmigration was associated with the production of a cleaved form of the cell adhesion protein E-cadherin, and pretreatment of the neutrophils with an inhibitor of the enzyme elastase reduced E-cadherin cleavage and prevented nuclear translocation of β-catenin, activation of the reporter gene and endogenous β-catenin target genes, and epithelial repair. Epithelial injury was more extensive, and repair was delayed after transmigration of the neutrophils when β-catenin was knocked down in epithelial cells. Neutrophil infiltration stimulated β-catenin activity in lung epithelial cells in a mouse model of lung injury. Furthermore, intratracheal treatment with a neutrophil chemoattractant in the absence of injury increased the abundance of cyclin D1, which is encoded by a β-catenin target gene, and this response was absent if the mice were pretreated with an antibody to deplete neutrophils. Thus, neutrophil transmigration produces elastase-mediated cleavage of adhesion proteins, which not only disrupts the epithelial barrier but also releases β-catenin to trigger expression of genes necessary for epithelial proliferation and repair.

R. L. Zemans, N. Briones, M. Campbell, J. McClendon, S. K. Young, T. Suzuki, I. V. Yang, S. De Langhe, S. D. Reynolds, R. J. Mason, M. Kahn, P. M. Henson, S. P. Colgan, G. P. Downey, Neutrophil transmigration triggers repair of the lung epithelium via β-catenin signaling. Proc. Natl. Acad. Sci. U.S.A. 108, 15990–15995 (2011). [PubMed]

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