The FMS-like tyrosine kinase-3 ligand/lung dendritic cell axis contributes to regulation of pulmonary fibrosis

Abstract

RationaleDendritic cells (DC) accumulate in the lungs of patients with idiopathic lung fibrosis, but their pathogenetic relevance is poorly defined.ObjectivesTo assess the role of the FMS-like tyrosine kinase-3 ligand (Flt3L)-lung dendritic cell axis in lung fibrosis.Measurements and main resultsWe 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.ConclusionsWe 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.

Disparate Interferon Signaling and Shared Aberrant Basaloid Cells in Single-Cell Profiling of Idiopathic Pulmonary Fibrosis and Systemic Sclerosis-Associated Interstitial Lung Disease

“…In the murine bleomycin skin and lung fibrosis models, reduction of pDCs results in decreased inflammation and fibrosis, indicating their potential as a therapeutic target in fibrosis ( 59 ). Murine studies and the accumulation of conventional dendritic cells (cDCs) in the BAL fluid of patients with IPF have implicated cDC dysfunction in the pathogenesis of IPF, however the role of pDCs in IPF is much less defined ( 62 , 63 ). In our analysis, although pDCs were recovered from the lung at similar frequencies for both IPF and SSc-ILD, the SSc-ILD pDCs were more transcriptionally active, expressed greater type 1 interferon receptor, and upregulation of multiple cellular stress response pathways.…”

Dendritic Cells Are the Intriguing Players in the Puzzle of Idiopathic Pulmonary Fibrosis Pathogenesis

“…In a clinical trial published in 2015, the DC-specific growth factor Flt3L was found to increase cDC1 and cDC2 cell populations' precursors in bone marrow biopsies and peripheral blood samples from healthy volunteers (64). Following this finding, Flt3L has further been shown to be up-regulated in the serum and lung tissue of IPF patients, likely contributing to the accumulation of lung DCs during pulmonary fibrogenesis (65).…”

“…Accordingly, recent clinical trials have explored the safety and efficacy of recombinant human Flt3L in healthy volunteers and cancer therapy to trigger DC expansion in humans (79)(80)(81). Interestingly, recombinant Flt3L increased the numbers of CD11b + DCs, reducing lung fibrosis in wild-type (WT) mice exposed to AdTGF-beta1 (65).…”

The Roles of Immune Cells in the Pathogenesis of Fibrosis

“…Selective depletion of lung DCs markedly exacerbated lung fibrosis in mice, suggesting a protective role of lung DCs in fibrogenesis [ 59 ]. Furthermore, increased mobilization of lung CD11b + DC regulated pulmonary fibrosis development in mice [ 60 ]. These studies have suggested the potential of DC-based immunotherapy for the treatment of lung fibrosis.…”