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

Abstract

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 up-regulated 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 up-regulation 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.

The IFITM protein family in adaptive immunity

“…70,71 Given the link between IFITM and Hh signalling and the fact that Hh signalling has also been shown to promote Th2 differentiation and exacerbate allergic asthma, it will be important to investigate the interactions between IFITM proteins and the Hh pathway in allergic asthma. 11,[72][73][74][75][76][77] The IFITM proteins are associated with other atopic and inflammatory diseases. In atopic dermatitis patients, IFITM1-3 are up-regulated in lesional skin compared with non-lesional skin from the same individuals, although the functional consequences of their increased expression have not been investigated.…”

“…The role of IFITM proteins in human allergic asthma has to our knowledge not been investigated, but genome‐wide association studies have linked IFITM2 and/or IFITM3 variants to potentially relevant traits, such as the proportion or count of basophils and eosinophils in blood, and lung function . Given the link between IFITM and Hh signalling and the fact that Hh signalling has also been shown to promote Th2 differentiation and exacerbate allergic asthma, it will be important to investigate the interactions between IFITM proteins and the Hh pathway in allergic asthma …”

Sonic hedgehog signalling as a potential endobronchial biomarker in COPD

“…HH signalling occurs upon Shh ligand binding and leads to Gli2 nuclear translocation, mainly described as an activator of transcription [ 9 ]. HH pathway signalling alterations have been observed in respiratory diseases such as pulmonary fibrosis [ 10 , 11 ], asthma [ 12 , 13 ] and lung cancer [ 14 ]. We recently demonstrated that the HH pathway was inextricably linked to airway epithelial cell (AEC) differentiation in adulthood [ 15 ].…”

Epigenome-wide association study identifies DNA methylation markers for asthma remission in whole blood and nasal epithelium

“…In whole blood, 99 eQTM genes that were associated with ComR were enriched in eight pathways, among which three pathways were related to airway epithelial function: activation of SMO (Smoothen), cilium assembly and focal adhesion. The activation of SMO activity in bronchial epithelia enhanced the allergen-induced goblet cell metaplasia, which is defined as a reversible transformation of airway epithelial cells to mucous cells such as goblet cells and may occur in asthma [ 34 ]. Airway cilia are important for clearance of inhaled particles and pathogens.…”