Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis.
Pulmonary fibrosis, in particular idiopathic pulmonary fibrosis (IPF), results from aberrant wound healing and scarification. One population of fibroblasts involved in the fibrotic process is thought to originate from lung epithelial cells via epithelial-mesenchymal transition (EMT). Indeed, alveolar epithelial cells (AECs) undergo EMT in vivo during experimental fibrosis and ex vivo in response to TGF-beta1. As the ECM critically regulates AEC responses to TGF-beta1, we explored the role of the prominent epithelial integrin alpha3beta1 in experimental fibrosis by generating mice with lung epithelial cell-specific loss of alpha3 integrin expression. These mice had a normal acute response to bleomycin injury, but they exhibited markedly decreased accumulation of lung myofibroblasts and type I collagen and did not progress to fibrosis. Signaling through beta-catenin has been implicated in EMT; we found that in primary AECs, alpha3 integrin was required for beta-catenin phosphorylation at tyrosine residue 654 (Y654), formation of the pY654-beta-catenin/pSmad2 complex, and initiation of EMT, both in vitro and in vivo during the fibrotic phase following bleomycin injury. Finally, analysis of lung tissue from IPF patients revealed the presence of pY654-beta-catenin/pSmad2 complexes and showed accumulation of pY654-beta-catenin in myofibroblasts. These findings demonstrate epithelial integrin-dependent profibrotic crosstalk between beta-catenin and Smad signaling and support the hypothesis that EMT is an important contributor to pathologic fibrosis.
Kim
Kevin K
KK
Pulmonary and Critical Care Division, Department of Medicine, and Cardiovascular Research Institute, UCSF, San Francisco, CA 94143, USA.
Wei
Ying
Y
Szekeres
Charles
C
Kugler
Matthias C
MC
Wolters
Paul J
PJ
Hill
Marla L
ML
Frank
James A
JA
Brumwell
Alexis N
AN
Wheeler
Sarah E
SE
Kreidberg
Jordan A
JA
Chapman
Harold A
HA
D055371:Acute Lung Injury / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D039201:Integrin alpha3beta1 / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008648:Mesoderm / Q000166:cytology / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D039201:Integrin alpha3beta1; D051899:Smad2 Protein; D051176:beta Catenin; D001761:Bleomycin