Abstract
TGF-β1 is a major mediator of airway tissue remodelling during atopic asthma and affects tight junctions (TJs) of airway epithelia. However, its impact on TJs of ciliated epithelia is sparsely investigated. Herein we elaborated effects of TGF-β1 on TJs of primary human bronchial epithelial cells. We demonstrate that TGF-β1 activates TGF-β1 receptors TGFBR1 and TGFBR2 resulting in ALK5-mediated phosphorylation of SMAD2. We observed that TGFBR1 and -R2 localize specifically on motile cilia. TGF-β1 activated accumulation of phosphorylated SMAD2 (pSMAD2-C) at centrioles of motile cilia and at cell nuclei. This triggered an increase in paracellular permeability via cellular redistribution of claudin 3 (CLDN3) from TJs into cell nuclei followed by disruption of epithelial integrity and formation of epithelial lesions. Only ciliated cells express TGF-β1 receptors; however, nuclear accumulations of pSMAD2-C and CLDN3 redistribution were observed with similar time course in ciliated and non-ciliated cells. In summary, we demonstrate a role of motile cilia in TGF-β1 sensing and showed that TGF-β1 disturbs TJ permeability of conductive airway epithelia by redistributing CLDN3 from TJs into cell nuclei. We conclude that the observed effects contribute to loss of epithelial integrity during atopic asthma.
Highlights
Enrichment of eosinophils is commonly observed in lungs of patients with atopic asthma [3] and contributes substantially to airway remodelling [46]
We demonstrated that TGF-β1 is sensed by motile cilia that are decorated with TGF-β1 receptors 1 and 2 (TGFBR1 and TGFBR2, respectively) and acts on tight junctions (TJs) via its canonical SMAD2-dependent signalling pathway
Between day 22 and 23, TGF-β1 transepithelial electrical resistance (TEER) further declined in TGF-β1-treated epithelia while no change in TEER was observed in control epithelia
Summary
Enrichment of eosinophils is commonly observed in lungs of patients with atopic asthma [3] and contributes substantially to airway remodelling [46]. Eosinophils have been identified as a major source of TGF-β1 in the lung [73]. Eosinophil-derived TGF-β1 was identified as a major factor that triggers tissue remodelling in atopic asthma [39]. Transforming growth factors β (TGF-β) constitute a subgroup of the transforming growth factor superfamily. Three TGF-β isoforms have been identified so far, TGF-β1, -β2 and -β3 [42]. All members of transforming growth factor superfamily are synthesized as pre-pro-peptides that consist of a Pflugers Arch - Eur J Physiol (2021) 473:287–311 the co-SMAD SMAD-4 to form protein complexes that translocate into the nucleus and exhibit transcriptional activity
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
