Motile cilia of human airway epithelia mediate noncanonical hedgehog signaling

Primary cilia are single sensory microtubule organelles present on most eukaryotic cells and are important for Sonic Hedgehog (SHH) signaling transduction in embryo development. In respiratory system, SHH signaling is essential for regulating lung development and maintaining homeostasis in adult lung. Unlike many cell types that have a single primary cilium, respiratory airway epithelia can contain multiple motile cilia. However, whether airway epithelia have apical receptors for SHH has remained unknown. Here, we found that motile cilia on airway epithelial cells have SHH signaling components, including receptor Patched 1, effector Smoothened and regulator GLI2/3. These cilia also have proteins involved in cAMP signaling, including Gαi and adenlyly cyclase 5/6. Surprisingly, SHH in differentiated airway epithelia did not elicit the canonical SHH signaling pathway that regulates transcription during development. Instead, we identified a non-canonical SHH signaling pathway that reduced intracellular cAMP levels. As a result, SHH signaling decreased cAMP-dependent ciliary beating, inhibited cAMP-activated CFTR current activity, and reduced airway surface liquid pH, similar to changes that have been observed in the airway of people with chronic obstructive pulmonary disease (COPD). Additionally, in differentiated cultures of human airway epithelia obtained from people with COPD, we observed significant increase of SHH ligand expression. Collectively, our data suggests that SHH may signal motile cilia to mediate noncanonical SHH signaling in order to dampen respiratory defenses at the contact point between the environment and the lung. Our finding indicates a potential role of SHH signaling in the pathogenesis of airway disease, such as COPD.