Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 6, Pages 1370-1375Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1719177115
Keywords
lung; cAMP; host defense; smoothened; sonic hedgehog
Categories
Funding
- National Institutes of Health [HL09184, HL51670]
- Cystic Fibrosis Foundation Research Development Program
- Roy J. Carver Charitable Trust
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Differentiated airway epithelia produce sonic hedgehog (SHH), which is found in the thin layer of liquid covering the airway surface. Although previous studies showed that vertebrate HH signaling requires primary cilia, as airway epithelia mature, the cells lose primary cilia and produce hundreds of motile cilia. Thus, whether airway epithelia have apical receptors for SHH has remained unknown. We discovered that motile cilia on airway epithelial cells have HH signaling proteins, including patched and smoothened. These cilia also have proteins affecting cAMP-dependent signaling, including G alpha(i) and adenylyl cyclase 5/6. Apical SHH decreases intracellular levels of cAMP, which reduces ciliary beat frequency and pH in airway surface liquid. These results suggest that apical SHH may mediate noncanonical HH signaling through motile cilia to dampen respiratory defenses at the contact point between the environment and the lung, perhaps counter-balancing processes that stimulate airway defenses.
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