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

doi:10.1164/rccm.201303-0434OC

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 journal › Article › peer-review

51 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 language	English
Pages (from-to)	831-841
Number of pages	11
Journal	American journal of respiratory and critical care medicine
Volume	188
Issue number	7
DOIs	https://doi.org/10.1164/rccm.201303-0434OC
State	Published - Oct 1 2013

Keywords

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

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10.1164/rccm.201303-0434OC

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Shi, Y., Gochuico, B. R., Yu, G., Tang, X., Osorio, J. C., Fernandez, I. E., Risquez, C. F., Patel, A. S., Shi, Y., Wathelet, M. G., Goodwin, A. J., Haspel, J. A., Ryter, S. W., Billings, E. M., Kaminski, N., Morse, D., & Rosas, I. O. (2013). Syndecan-2 exerts antifibrotic effects by promoting caveolin-1-mediated transforming growth factor-b receptor i internalization and inhibiting transforming growth factor-b1 signaling. American journal of respiratory and critical care medicine, 188(7), 831-841. https://doi.org/10.1164/rccm.201303-0434OC

@article{5d9156c0b82d4297be6b9fbfd67e7d03,

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

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.",

keywords = "Alveolar macrophage, Idiopathic pulmonary fibrosis, Syndecan-2, TGF-b1 signaling",

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

year = "2013",

month = oct,

day = "1",

doi = "10.1164/rccm.201303-0434OC",

language = "English",

volume = "188",

pages = "831--841",

journal = "American journal of respiratory and critical care medicine",

issn = "1073-449X",

number = "7",

}

Shi, Y, Gochuico, BR, Yu, G, Tang, X, Osorio, JC, Fernandez, IE, Risquez, CF, Patel, AS, Shi, Y, Wathelet, MG, Goodwin, AJ, Haspel, JA, Ryter, SW, Billings, EM, Kaminski, N, Morse, D & Rosas, IO 2013, 'Syndecan-2 exerts antifibrotic effects by promoting caveolin-1-mediated transforming growth factor-b receptor i internalization and inhibiting transforming growth factor-b1 signaling', American journal of respiratory and critical care medicine, vol. 188, no. 7, pp. 831-841. https://doi.org/10.1164/rccm.201303-0434OC

Syndecan-2 exerts antifibrotic effects by promoting caveolin-1-mediated transforming growth factor-b receptor i internalization and inhibiting transforming growth factor-b1 signaling. / Shi, Yuanyuan; Gochuico, Bernadette R.; Yu, Guoying et al.
In: American journal of respiratory and critical care medicine, Vol. 188, No. 7, 01.10.2013, p. 831-841.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Syndecan-2 exerts antifibrotic effects by promoting caveolin-1-mediated transforming growth factor-b receptor i internalization and inhibiting transforming growth factor-b1 signaling

AU - Shi, Yuanyuan

AU - Gochuico, Bernadette R.

AU - Yu, Guoying

AU - Tang, Xiaomeng

AU - Osorio, Juan C.

AU - Fernandez, Isis E.

AU - Risquez, Cristobal F.

AU - Patel, Avignat S.

AU - Shi, Ying

AU - Wathelet, Marc G.

AU - Goodwin, Andrew J.

AU - Haspel, Jeffrey A.

AU - Ryter, Stefan W.

AU - Billings, Eric M.

AU - Kaminski, Naftali

AU - Morse, Danielle

AU - Rosas, Ivan O.

PY - 2013/10/1

Y1 - 2013/10/1

N2 - 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.

AB - 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.

KW - Alveolar macrophage

KW - Idiopathic pulmonary fibrosis

KW - Syndecan-2

KW - TGF-b1 signaling

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U2 - 10.1164/rccm.201303-0434OC

DO - 10.1164/rccm.201303-0434OC

M3 - Article

C2 - 23924348

AN - SCOPUS:84886286233

SN - 1073-449X

VL - 188

SP - 831

EP - 841

JO - American journal of respiratory and critical care medicine

JF - American journal of respiratory and critical care medicine

IS - 7

ER -

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

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