Syndecan-2 exerts antifibrotic effects by promoting caveolin-1-mediated transforming growth factor-β receptor I internalization and inhibiting transforming growth factor-β1 signaling.
BACKGROUND
Alveolar transforming growth factor (TGF)-β1 signaling and expression of TGF-β1 target genes are increased in patients with idiopathic pulmonary fibrosis (IPF) and in animal models of pulmonary fibrosis. Internalization and degradation of TGF-β receptor TβRI inhibits TGF-β signaling and could attenuate development of experimental lung fibrosis.


OBJECTIVE
To demonstrate that after experimental lung injury, human syndecan-2 confers antifibrotic effects by inhibiting TGF-β1 signaling in alveolar epithelial cells.


METHODS
Microarray assays were performed to identify genes differentially expressed in alveolar macrophages of patients with IPF versus control subjects. Transgenic mice that constitutively overexpress human syndecan-2 in macrophages were developed to test the antifibrotic properties of syndecan-2. In vitro assays were performed to determine syndecan-2-dependent changes in epithelial cell TGF-β1 signaling, TGF-β1, and TβRI internalization and apoptosis. Wild-type mice were treated with recombinant human syndecan-2 during the fibrotic phase of bleomycin-induced lung injury.


RESULTS
We observed significant increases in alveolar macrophage syndecan-2 levels in patients with IPF. Macrophage-specific overexpression of human syndecan-2 in transgenic mice conferred antifibrotic effects after lung injury by inhibiting TGF-β1 signaling and downstream expression of TGF-β1 target genes, reducing extracellular matrix production and alveolar epithelial cell apoptosis. In vitro, syndecan-2 promoted caveolin-1-dependent internalization of TGF-β1 and TβRI in alveolar epithelial cells, which inhibited TGF-β1 signaling and epithelial cell apoptosis. Therapeutic administration of human syndecan-2 abrogated lung fibrosis in mice.


CONCLUSIONS
Alveolar macrophage syndecan-2 exerts antifibrotic effects by promoting caveolin-1-dependent TGF-β1 and TβRI internalization and inhibiting TGF-β1 signaling in alveolar epithelial cells. Hence, molecules that facilitate TβRI degradation via endocytosis represent potential therapies for pulmonary fibrosis.
1 Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Yuanyuan
Y
Shi
Bernadette R
BR
Gochuico
Guoying
G
Yu
Xiaomeng
X
Tang
Juan C
JC
Osorio
Isis E
IE
Fernandez
Cristobal F
CF
Risquez
Avignat S
AS
Patel
Ying
Y
Shi
Marc G
MG
Wathelet
Andrew J
AJ
Goodwin
Jeffrey A
JA
Haspel
Stefan W
SW
Ryter
Eric M
EM
Billings
Naftali
N
Kaminski
Danielle
D
Morse
Ivan O
IO
Rosas
D000818:Animals; D017209:Apoptosis; D001761:Bleomycin / Q000008:administration & dosage; D018893:Bronchoalveolar Lavage; D051242:Caveolin 1 / Q000187:drug effects; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005819:Genetic Markers; D006801:Humans; D006909:Hydroxyproline / Q000032:analysis; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced* / Q000188:drug therapy / Q000235:genetics; D066298:In Vitro Techniques; D016676:Macrophages, Alveolar / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction; D053669:Syndecan-2 / Q000502:physiology / Q000627:therapeutic use*; D046888:Tissue Array Analysis; D053773:Transforming Growth Factor beta1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D051242:Caveolin 1; D005819:Genetic Markers; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D053669:Syndecan-2; D006909:Hydroxyproline