TY - JOUR
T1 - miR449 Protects Airway Regeneration by Controlling AURKA/HDAC6-Mediated Ciliary Disassembly
AU - Wildung, Merit
AU - Herr, Christian
AU - Riedel, Dietmar
AU - Wiedwald, Cornelia
AU - Moiseenko, Alena
AU - Ramírez, Fidel
AU - Tasena, Hataitip
AU - Heimerl, Maren
AU - Alevra, Mihai
AU - Movsisyan, Naira
AU - Schuldt, Maike
AU - Volceanov-Hahn, Larisa
AU - Provoost, Sharen
AU - Nöthe-Menchen, Tabea
AU - Urrego, Diana
AU - Freytag, Bernard
AU - Wallmeier, Julia
AU - Beisswenger, Christoph
AU - Bals, Robert
AU - van den Berge, Maarten
AU - Timens, Wim
AU - Hiemstra, Pieter S
AU - Brandsma, Corry-Anke
AU - Maes, Tania
AU - Andreas, Stefan
AU - Heijink, Irene H
AU - Pardo, Luis A
AU - Lizé, Muriel
PY - 2022/7/13
Y1 - 2022/7/13
N2 - 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.
AB - 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.
KW - Animals
KW - Aurora Kinase A/genetics
KW - Cilia/genetics
KW - Epithelial Cells
KW - Mice
KW - MicroRNAs/genetics
KW - Pulmonary Disease, Chronic Obstructive/genetics
KW - Tubulin/genetics
U2 - 10.3390/ijms23147749
DO - 10.3390/ijms23147749
M3 - Article
C2 - 35887096
VL - 23
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1422-0067
IS - 14
M1 - 7749
ER -