High-mobility group box 1 impairs airway epithelial barrier function through the activation of the RAGE/ERK pathway

• Published in: International journal of molecular medicine 2016-05, Vol.37 (5), p.1189-1198
• Main Authors: HUANG, WUFENG, ZHAO, HAIJIN, DONG, HANGMING, WU, YUE, YAO, LIHONG, ZOU, FEI, CAI, SHAOXI
• Format: Article
• Language: English
• Subjects: Asthma; cell adhesion molecules; Cells; Cellular signal transduction; Cytokines; epithelial cell biology; epithelial injury; Genetic aspects; Genetic regulation; Health aspects; Hogs; Inflammatory diseases; inflammatory mediators in asthma; Kinases; Lung diseases; lung epithelial permeability; Observations; Pathogenesis; Permeability; Properties; Proteins; Small intestine; Studies; Transcription factors
• ISSN: 1107-3756; 1791-244X
• DOI: 10.3892/ijmm.2016.2537

Recent studies have indicated that high-mobility group box 1 protein (HMGB1) and the receptor for advanced glycation end-products (RAGE) contribute to the pathogenesis of asthma. However, whether the activation of the HMGB1/RAGE axis mediates airway epithelial barrier dysfunction remains unknown. Thus, the aim of this study was to examine the effects of HMGB1 and its synergistic action with interleukin (IL)-1β on airway epithelial barrier properties. We evaluated the effects of recombinant human HMGB1 alone or in combination with IL-1β on ionic and macromolecular barrier permeability, by culturing air-liquid interface 16HBE cells with HMGB1 to mimic the differentiated epithelium. Western blot analysis and immunofluorescence staining were utilized to examine the level and structure of major junction proteins, namely E-cadherin, β-catenin, occludin and claudin-1. Furthermore, we examined the effects of RAGE neutralizing antibodies and mitogen-activated protein kinase (MAPK) inhibitors on epithelial barrier properties in order to elucidate the mechanisms involved. HMGB1 increased FITC-dextran permeability, but suppressed epithelial resistance in a dose-and time-dependent manner. HMGB1-mediated barrier hyperpermeability was accompanied by a disruption of cell-cell contacts, the selective downregulation of occludin and claudin-1, and the redistribution of E-cadherin and β-catenin. HMGB1 in synergy with IL-1β induced a similar, but greater barrier hyperpermeability and induced the disruption of junction proteins. Furthermore, HMGB1 elicited the activation of the RAGE/extracellular signal-related kinase (ERK)1/2 signaling pathway, which correlated with barrier dysfunction in the 16HBE cells. Anti-RAGE antibody and the ERK1/2 inhibitor, U0126, attenuated the HMGB1-mediated changes in barrier permeability, restored the expression levels of occludin and claudin-1 and pevented the redistribution of E-cadherin and β-catenin. Taken together, the findings of our study demonstrate that HMGB1 is capable of inducing potent effects on epithelial barrier function and that RAGE/ERK1/2 is a key signaling pathway involved in the crosstalk between formations of junction proteins and epithelial barrier dysfunction.