Airway mucociliary regeneration and function are key players for airway defense and
are impaired in chronic obstructive pulmonary disease (COPD). Using transcriptome analysis in
COPD-derived bronchial biopsies, we observed a positive correlation between cilia-related genes
and microRNA-449 (miR449). In vitro, miR449 was strongly increased during airway epithelial
mucociliary differentiation. In vivo, miR449 was upregulated during recovery from chemical or
infective insults. miR0449−/− mice (both alleles are deleted) showed impaired ciliated epithelial
regeneration after naphthalene and Haemophilus influenzae exposure, accompanied by more intense
inflammation and emphysematous manifestations of COPD. The latter occurred spontaneously
in aged miR449−/− mice. We identified Aurora kinase A and its effector target HDAC6 as key
mediators in miR449-regulated ciliary homeostasis and epithelial regeneration. Aurora kinase A is
downregulated upon miR449 overexpression in vitro and upregulated in miR449−/− mouse lungs.
Accordingly, imaging studies showed profoundly altered cilia length and morphology accompanied
by reduced mucociliary clearance. Pharmacological inhibition of HDAC6 rescued cilia length and
coverage in miR449−/− cells, consistent with its tubulin-deacetylating function. Altogether, our study
establishes a link between miR449, ciliary dysfunction, and COPD pathogenesis