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S100a4 Is Secreted by Alternatively Activated Alveolar Macrophages and Promotes Activation of Lung Fibroblasts in Pulmonary Fibrosis

Zhang, Wei LU ; Ohno, Shinji; Steer, Beatrix; Klee, Stephan; Staab-Weijnitz, Claudia A; Wagner, Darcy LU ; Lehmann, Mareike; Stoeger, Tobias; Königshoff, Melanie and Adler, Heiko (2018) In Frontiers in Immunology 9. p.1-14
Abstract

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease, characterized by damage of lung epithelial cells, excessive deposition of extracellular matrix in the lung interstitium, and enhanced activation and proliferation of fibroblasts. S100a4, also termed FSP-1 (fibroblast-specific protein-1), was previously considered as a marker of fibroblasts but recent findings in renal and liver fibrosis indicated that M2 macrophages are an important cellular source of S100a4. Thus, we hypothesized that also in pulmonary fibrosis, M2 macrophages produce and secrete S100a4, and that secreted S100a4 induces the proliferation and activation of fibroblasts. To prove this hypothesis, we comprehensively characterized two... (More)

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease, characterized by damage of lung epithelial cells, excessive deposition of extracellular matrix in the lung interstitium, and enhanced activation and proliferation of fibroblasts. S100a4, also termed FSP-1 (fibroblast-specific protein-1), was previously considered as a marker of fibroblasts but recent findings in renal and liver fibrosis indicated that M2 macrophages are an important cellular source of S100a4. Thus, we hypothesized that also in pulmonary fibrosis, M2 macrophages produce and secrete S100a4, and that secreted S100a4 induces the proliferation and activation of fibroblasts. To prove this hypothesis, we comprehensively characterized two established mouse models of lung fibrosis: infection of IFN-γR-/- mice with MHV-68 and intratracheal application of bleomycin to C57BL/6 mice. We further provide in vitro data using primary macrophages and fibroblasts to investigate the mechanism by which S100A4 exerts its effects. Finally, we inhibit S100a4 in vivo in the bleomycin-induced lung fibrosis model by treatment with niclosamide. Our data suggest that S100a4 is produced and secreted by M2 polarized alveolar macrophages and enhances the proliferation and activation of lung fibroblasts. Inhibition of S100a4 might represent a potential therapeutic strategy for pulmonary fibrosis.

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author
publishing date
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publication status
published
in
Frontiers in Immunology
volume
9
pages
1 - 14
publisher
Frontiers Media S. A.
external identifiers
  • scopus:85047848794
ISSN
1664-3224
DOI
10.3389/fimmu.2018.01216
language
English
LU publication?
no
id
48da0fc2-868f-41ea-88dc-0498eaa19a3d
date added to LUP
2018-08-27 14:01:52
date last changed
2019-02-20 11:24:51
@article{48da0fc2-868f-41ea-88dc-0498eaa19a3d,
  abstract     = {<p>Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease, characterized by damage of lung epithelial cells, excessive deposition of extracellular matrix in the lung interstitium, and enhanced activation and proliferation of fibroblasts. S100a4, also termed FSP-1 (fibroblast-specific protein-1), was previously considered as a marker of fibroblasts but recent findings in renal and liver fibrosis indicated that M2 macrophages are an important cellular source of S100a4. Thus, we hypothesized that also in pulmonary fibrosis, M2 macrophages produce and secrete S100a4, and that secreted S100a4 induces the proliferation and activation of fibroblasts. To prove this hypothesis, we comprehensively characterized two established mouse models of lung fibrosis: infection of IFN-γR-/- mice with MHV-68 and intratracheal application of bleomycin to C57BL/6 mice. We further provide in vitro data using primary macrophages and fibroblasts to investigate the mechanism by which S100A4 exerts its effects. Finally, we inhibit S100a4 in vivo in the bleomycin-induced lung fibrosis model by treatment with niclosamide. Our data suggest that S100a4 is produced and secreted by M2 polarized alveolar macrophages and enhances the proliferation and activation of lung fibroblasts. Inhibition of S100a4 might represent a potential therapeutic strategy for pulmonary fibrosis.</p>},
  articleno    = {1216},
  author       = {Zhang, Wei and Ohno, Shinji and Steer, Beatrix and Klee, Stephan and Staab-Weijnitz, Claudia A and Wagner, Darcy and Lehmann, Mareike and Stoeger, Tobias and Königshoff, Melanie and Adler, Heiko},
  issn         = {1664-3224},
  language     = {eng},
  pages        = {1--14},
  publisher    = {Frontiers Media S. A.},
  series       = {Frontiers in Immunology},
  title        = {S100a4 Is Secreted by Alternatively Activated Alveolar Macrophages and Promotes Activation of Lung Fibroblasts in Pulmonary Fibrosis},
  url          = {http://dx.doi.org/10.3389/fimmu.2018.01216},
  volume       = {9},
  year         = {2018},
}