Syndecan-2 exerts antifibrotic effects by promoting caveolin-1-mediated transforming growth factor-b receptor i internalization and inhibiting transforming growth factor-b1 signaling

Yuanyuan Shi, Bernadette R. Gochuico, Guoying Yu, Xiaomeng Tang, Juan C. Osorio, Isis E. Fernandez, Cristobal F. Risquez, Avignat S. Patel, Ying Shi, Marc G. Wathelet, Andrew J. Goodwin, Jeffrey A. Haspel, Stefan W. Ryter, Eric M. Billings, Naftali Kaminski, Danielle Morse, Ivan O. Rosas

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Rationale: Alveolar transforming growth factor (TGF)-b1 signaling and expression of TGF-b1 target genes are increased in patients with idiopathic pulmonary fibrosis (IPF) and in animal models of pulmonary fibrosis. Internalization and degradation of TGF-b receptor TbRI inhibits TGF-b signaling and could attenuate development of experimental lung fibrosis. Objectives: To demonstrate that after experimental lung injury, humansyndecan- 2 confers antifibrotic effects by inhibiting TGF-b1 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-2dependent changes in epithelial cell TGF-b1 signaling, TGF-b1, and TbRI internalization and apoptosis. Wildtype mice were treated with recombinant human syndecan-2 during the fibrotic phase of bleomycin-induced lung injury. Measurements and Main 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-b1 signaling and downstream expression of TGF-b1 target genes, reducing extracellularmatrix production and alveolar epithelial cell apoptosis. In vitro, syndecan-2 promoted caveolin-1dependent internalization of TGF-b1 and TbRI in alveolar epithelial cells, which inhibited TGF-b1 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-1dependent TGF-b1 and TbRI internalization and inhibiting TGF-b1 signaling in alveolar epithelial cells. Hence, molecules that facilitate TbRI degradation via endocytosis represent potential therapies for pulmonary fibrosis.

Original languageEnglish
Pages (from-to)831-841
Number of pages11
JournalAmerican journal of respiratory and critical care medicine
Volume188
Issue number7
DOIs
StatePublished - Oct 1 2013

Keywords

  • Alveolar macrophage
  • Idiopathic pulmonary fibrosis
  • Syndecan-2
  • TGF-b1 signaling

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