Alternatively spliced myeloid differentiation protein-2 inhibits TLR4-mediated lung inflammation

• Published in: The Journal of immunology (1950) 2015-02, Vol.194 (4), p.1686-1694
• Main Authors: Tumurkhuu, Gantsetseg, Dagvadorj, Jargalsaikhan, Jones, Heather D, Chen, Shuang, Shimada, Kenichi, Crother, Timothy R, Arditi, Moshe
• Format: Article
• Language: English
• Subjects: Acute Lung Injury - genetics; Acute Lung Injury - immunology; Adenovirus; Alternative Splicing; Animals; Blotting, Western; Dermatophagoides pteronyssinus; Disease Models, Animal; Female; Flow Cytometry; Humans; Hypersensitivity - genetics; Hypersensitivity - immunology; Immunohistochemistry; Lymphocyte Antigen 96 - genetics; Lymphocyte Antigen 96 - immunology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pneumonia - genetics; Pneumonia - immunology; Protein Isoforms - genetics; Protein Isoforms - immunology; Real-Time Polymerase Chain Reaction; Toll-Like Receptor 4 - immunology; Transfection
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1402123

We previously identified a novel alternatively spliced isoform of human myeloid differentiation protein-2 (MD-2s) that competitively inhibits binding of MD-2 to TLR4 in vitro. In this study, we investigated the protective role of MD-2s in LPS-induced acute lung injury by delivering intratracheally an adenovirus construct that expressed MD-2s (Ad-MD-2s). After adenovirus-mediated gene transfer, MD-2s was strongly expressed in lung epithelial cells and readily detected in bronchoalveolar lavage fluid. Compared to adenovirus serotype 5 containing an empty vector lacking a transgene control mice, Ad-MD-2s delivery resulted in significantly less LPS-induced inflammation in the lungs, including less protein leakage, cell recruitment, and expression of proinflammatory cytokines and chemokines, such as IL-6, keratinocyte chemoattractant, and MIP-2. Bronchoalveolar lavage fluid from Ad-MD-2s mice transferred into lungs of naive mice before intratracheal LPS challenge diminished proinflammatory cytokine levels. As house dust mite (HDM) sensitization is dependent on TLR4 and HDM Der p 2, a structural homolog of MD-2, we also investigated the effect of MD-2s on HDM-induced allergic airway inflammation. Ad-MD-2s given before HDM sensitization significantly inhibited subsequent allergic airway inflammation after HDM challenge, including reductions in eosinophils, goblet cell hyperplasia, and IL-5 levels. Our study indicates that the alternatively spliced short isoform of human MD-2 could be a potential therapeutic candidate to treat human diseases induced or exacerbated by TLR4 signaling, such as Gram-negative bacterial endotoxin-induced lung injury and HDM-triggered allergic lung inflammation.