Gremlin-1 Overexpression in Mouse Lung Reduces Silica-Induced Lymphocyte Recruitment - A Link to Idiopathic Pulmonary Fibrosis through Negative Correlation with CXCL10 Chemokine

PLoS One. 2016 Jul 18;11(7):e0159010. doi: 10.1371/journal.pone.0159010. eCollection 2016.

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by activation and injury of epithelial cells, the accumulation of connective tissue and changes in the inflammatory microenvironment. The bone morphogenetic protein (BMP) inhibitor protein gremlin-1 is associated with the progression of fibrosis both in human and mouse lung. We generated a transgenic mouse model expressing gremlin-1 in type II lung epithelial cells using the surfactant protein C (SPC) promoter and the Cre-LoxP system. Gremlin-1 protein expression was detected specifically in the lung after birth and did not result in any signs of respiratory insufficiency. Exposure to silicon dioxide resulted in reduced amounts of lymphocyte aggregates in transgenic lungs while no alteration in the fibrotic response was observed. Microarray gene expression profiling and analyses of bronchoalveolar lavage fluid cytokines indicated a reduced lymphocytic response and a downregulation of interferon-induced gene program. Consistent with reduced Th1 response, there was a downregulation of the mRNA and protein expression of the anti-fibrotic chemokine CXCL10, which has been linked to IPF. In human IPF patient samples we also established a strong negative correlation in the mRNA expression levels of gremlin-1 and CXCL10. Our results suggest that in addition to regulation of epithelial-mesenchymal crosstalk during tissue injury, gremlin-1 modulates inflammatory cell recruitment and anti-fibrotic chemokine production in the lung.

MeSH terms

  • Animals
  • Cell Line
  • Chemokine CXCL10 / analysis
  • Chemokine CXCL10 / immunology*
  • Humans
  • Idiopathic Pulmonary Fibrosis / genetics
  • Idiopathic Pulmonary Fibrosis / immunology*
  • Idiopathic Pulmonary Fibrosis / pathology
  • Intercellular Signaling Peptides and Proteins / analysis
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Interferons / immunology
  • Lung / immunology*
  • Lung / pathology
  • Lymphocytes / immunology*
  • Lymphocytes / pathology
  • Mice
  • Mice, Transgenic
  • Silicon Dioxide / immunology
  • Up-Regulation*

Substances

  • Chemokine CXCL10
  • GREM1 protein, human
  • Grem1 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Silicon Dioxide
  • Interferons

Grants and funding

KK and MM are supported by the Jane and Aatos Erkko foundation, the Sigrid Jusélius Foundation and the University of Helsinki Research Fund. KK is supported by the Magnus Ehrnrooth foundation. MM is supported by the Helsinki University Hospital Research Fund. VP is supported by the Sigrid Jusélius Foundation. DG is supported by the Academy of Finland (grant number 275151 and 292307) and the European Commission, under grant agreement FP7-309329 (NANOSOLUTIONS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.