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The FMS-like tyrosine kinase-3 ligand/lung dendritic cell axis contributes to regulation of pulmonary fibrosis
  1. Meritxell Tort Tarrés1,
  2. Franziska Aschenbrenner1,
  3. Regina Maus1,
  4. Jennifer Stolper1,
  5. Lisanne Schuette1,
  6. Lars Knudsen2,3,
  7. Elena Lopez Rodriguez2,
  8. Danny Jonigk3,4,
  9. Mark Philipp Kühnel4,
  10. David DeLuca3,
  11. Antje Prasse5,
  12. Tobias Welte3,5,
  13. Jack Gauldie6,
  14. Martin RJ Kolb7,
  15. Ulrich A Maus1,3
  1. 1 Department of Experimental Pneumology, Hannover Medical School, Hannover, Germany
  2. 2 Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany
  3. 3 German Center for Lung Research, Partner site BREATH (Biomedical research in endstage and obstructive lung disease Hannover), Hannover Medical School, Hannover, Germany
  4. 4 Institute of Pathology, Hannover Medical School, Hannover, Germany
  5. 5 Clinic of Pneumology, Hannover Medical School, Hannover, Germany
  6. 6 Department of Pathology, McMaster University, Hamilton, Ontario, Canada
  7. 7 Department of Medicine, McMaster University, Hamilton, Ontario, Canada
  1. Correspondence to Professor Ulrich A Maus, Department of Experimental Pneumology, Hannover Medical School, Hannover 30625, Germany; Maus.Ulrich{at}


Rationale Dendritic cells (DC) accumulate in the lungs of patients with idiopathic lung fibrosis, but their pathogenetic relevance is poorly defined.

Objectives To assess the role of the FMS-like tyrosine kinase-3 ligand (Flt3L)-lung dendritic cell axis in lung fibrosis.

Measurements and main results We demonstrate in a model of adenoviral gene transfer of active TGF-β1 that established lung fibrosis was accompanied by elevated serum Flt3L levels and subsequent accumulation of CD11bpos DC in the lungs of mice. Patients with idiopathic pulmonary fibrosis also demonstrated increased levels of Flt3L protein in serum and lung tissue and accumulation of lung DC in explant subpleural lung tissue specimen. Mice lacking Flt3L showed significantly reduced lung DC along with worsened lung fibrosis and reduced lung function relative to wild-type (WT) mice, which could be inhibited by administration of recombinant Flt3L. Moreover, therapeutic Flt3L increased numbers of CD11bpos DC and improved lung fibrosis in WT mice exposed to AdTGF-β1. In this line, RNA-sequencing analysis of CD11bpos DC revealed significantly enriched differentially expressed genes within extracellular matrix degrading enzyme and matrix metalloprotease gene clusters. In contrast, the CD103pos DC subset did not appear to be involved in pulmonary fibrogenesis.

Conclusions We show that Flt3L protein and numbers of lung DC are upregulated in mice and humans during pulmonary fibrogenesis, and increased mobilisation of lung CD11bpos DC limits the severity of lung fibrosis in mice. The current study helps to inform the development of DC-based immunotherapy as a novel intervention against lung fibrosis in humans.

  • flt3l
  • dendritic cells
  • fibrosis
  • lung
  • MMP

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  • MRK and UAM are joint senior authors.

  • Contributors MTT carried out experiments, analysed the data and wrote the manuscript; FA, RM, JS, LS, LK, ELR and MK carried out experiments, DJ and DSD analysed the data, AP, TW, JG, MK and UAM designed the study, analysed the data and wrote the manuscript.

  • Funding The current study was financially supported by the Federal Ministry of Education and Research in support of the German Center for Lung Research, partner site Breath (Biomedical Research in Endstage and Obstructive Lung Disease Hannover).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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