High expression of Sonic hedgehog in allergic airway epithelia contributes to goblet cell metaplasia

• Published in: Mucosal immunology Vol. 11; no. 5; pp. 1306 - 1315
• Main Authors: Xu, Chengyun, Zou, Chaochun, Hussain, Musaddique, Shi, Wei, Shao, Yanan, Jiang, Ziyan, Wu, Xiling, Lu, Meiping, Wu, Junsong, Xie, Qiangmin, Ke, Yuehai, Long, Fanxin, Tang, Lanfang, Wu, Ximei
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2018; Elsevier Limited
• Subjects: Allergens; Allergic diseases; Allergology; Animal models; Animals; Antibodies; Antibodies, Neutralizing - immunology; Asthma; Asthma - genetics; Asthma - immunology; Asthma - pathology; Biomedical and Life Sciences; Biomedicine; Cell culture; Child; Child, Preschool; Disease; Embryos; Epithelial Cells - immunology; Epithelial Cells - pathology; ETS protein; Female; Forkhead protein; Gastroenterology; Gene Expression - genetics; Glycoproteins; Goblet Cells - immunology; Goblet Cells - pathology; Hedgehog protein; Hedgehog Proteins - genetics; Humans; Hypersensitivity - genetics; Hypersensitivity - immunology; Hypersensitivity - pathology; Immunology; Male; Metaplasia; Metaplasia - genetics; Metaplasia - immunology; Metaplasia - pathology; Mice; Mice, Inbred C57BL; Morphogenesis; Mucin; Mucin 5AC - genetics; Phenotypes; Respiratory Mucosa - immunology; Respiratory Mucosa - pathology; Respiratory tract diseases; Small intestine; Trachea; Transcription factors; Transcription Factors - genetics; Up-Regulation - genetics; Up-Regulation - immunology
• ISSN: 1933-0219; 1935-3456
• DOI: 10.1038/s41385-018-0033-4

Sonic hedgehog (SHH) is abundantly expressed and critical for morphogenesis in embryonic lungs; however, SHH expression drops to a much lower level in mice from E17.5 and in humans from the 21st gestational week. We find that SHH expression is robustly upregulated in the airway epithelia of children with asthma or mouse models with allergic airway disease. Specifically, airway-specific SMO loss of function significantly suppresses allergen-induced goblet cell phenotypes, whereas an airway-specific SMO gain of function markedly enhances the goblet cell phenotypes in mouse models with allergic airway disease. Notably, intratracheal administration with SHH-neutralizing antibody or cyclopamine robustly attenuates goblet cell phenotypes in mouse models with allergic airway disease. Finally, we identify that Muc5AC gene encoding MUC5AC mucin serves as a direct target of GLI transcriptional factors in response to SHH, whereas the SAM-pointed domain-containing ETS transcription factor and Forkhead box A2, critical transcriptional factors for goblet cell phenotypes, both function as the effectors of GLIs in response to SHH stimulation. Together, the upregulation of SHH expression in allergic bronchial epithelia contributes to goblet cell metaplasia; thus, blockage of SHH signaling is a rational approach in a therapeutic intervention of epithelial remodeling in chronic airway diseases.