Neutrophil transmigration triggers repair of the lung epithelium via β-catenin signaling

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-09, Vol.108 (38), p.15990-15995
• Main Authors: Zemans, Rachel L, Briones, Natalie, Campbell, Megan, McClendon, Jazalle, Young, Scott K, Suzuki, Tomoko, Yang, Ivana V, De Langhe, Stijn, Reynolds, Susan D, Mason, Robert J, Kahn, Michael, Henson, Peter M, Colgan, Sean P, Downey, Gregory P
• Format: Article
• Language: English
• Subjects: Alveoli; Animal models; Animals; beta Catenin - genetics; beta Catenin - metabolism; Biological Sciences; Cadherins; Cadherins - genetics; Cadherins - metabolism; catenin; Cell activation; Cell Line, Tumor; Cell migration; cell proliferation; Cells, Cultured; Chemokines; cyclin D1; Cyclins; E-Cadherin; elastase; Epithelial cells; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelium; Epithelium - injuries; Epithelium - metabolism; Epithelium - physiopathology; Female; Gene expression; Gene Expression Profiling; Humans; Immunoblotting; Inflammatory diseases; Injuries; Keratinocytes; Leukocyte elastase; Leukocyte migration; Leukocytes (neutrophilic); Lipopolysaccharides; Lung - metabolism; Lung - physiopathology; Lung diseases; Lungs; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; microarray technology; Neutrophils; Neutrophils - cytology; Neutrophils - physiology; Nuclear transport; Oligonucleotide Array Sequence Analysis; pathogenesis; Physical trauma; Polymerase chain reaction; Pulmonary alveoli; quantitative polymerase chain reaction; respiratory tract diseases; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction; Stem cells; Trachea; Transendothelial and Transepithelial Migration - physiology; Transmigration
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1110144108

Injury to the epithelium is integral to the pathogenesis of many inflammatory lung diseases, and epithelial repair is a critical determinant of clinical outcome. However, the signaling pathways regulating such repair are incompletely understood. We used in vitro and in vivo models to define these pathways. Human neutrophils were induced to transmigrate across monolayers of human lung epithelial cells in the physiological basolateral-to-apical direction. This allowed study of the neutrophil contribution not only to the initial epithelial injury, but also to its repair, as manifested by restoration of transepithelial resistance and reepithelialization of the denuded epithelium. Microarray analysis of epithelial gene expression revealed that neutrophil transmigration activated β-catenin signaling, and this was verified by real-time PCR, nuclear translocation of β-catenin, and TOPFlash reporter activity. Leukocyte elastase, likely via cleavage of E-cadherin, was required for activation of β-catenin signaling in response to neutrophil transmigration. Knockdown of β-catenin using shRNA delayed epithelial repair. In mice treated with intratracheal LPS or keratinocyte chemokine, neutrophil emigration resulted in activation of β-catenin signaling in alveolar type II epithelial cells, as demonstrated by cyclin D1 expression and/or reporter activity in TOPGAL mice. Attenuation of β-catenin signaling by IQ-1 inhibited alveolar type II epithelial cell proliferation in response to neutrophil migration induced by intratracheal keratinocyte chemokine. We conclude that β-catenin signaling is activated in lung epithelial cells during neutrophil transmigration, likely via elastase-mediated cleavage of E-cadherin, and regulates epithelial repair. This pathway represents a potential therapeutic target to accelerate physiological recovery in inflammatory lung diseases.