Fra-2–expressing macrophages promote lung fibrosis
Alvaro C. Ucero, … , Diego Megias, Erwin F. Wagner
Alvaro C. Ucero, … , Diego Megias, Erwin F. Wagner
Published May 28, 2019
Citation Information: J Clin Invest. 2019;129(8):3293-3309. https://doi.org/10.1172/JCI125366.
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Research Article Inflammation Pulmonology

Fra-2–expressing macrophages promote lung fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a deadly disease with limited therapies. Tissue fibrosis is associated with type 2 immune response, although the causal contribution of immune cells is not defined. The AP-1 transcription factor Fra-2 is upregulated in IPF lung sections, and Fra-2 transgenic mice (Fra-2Tg) exhibit spontaneous lung fibrosis. Here, we show that bleomycin-induced lung fibrosis is attenuated upon myeloid inactivation of Fra-2 and aggravated in Fra-2Tg bone marrow chimeras. Type VI collagen (ColVI), a Fra-2 transcriptional target, is upregulated in 3 lung fibrosis models, and macrophages promote myofibroblast activation in vitro in a ColVI- and Fra-2–dependent manner. Fra-2 or ColVI inactivation does not affect macrophage recruitment and alternative activation, suggesting that Fra-2/ColVI specifically controls the paracrine profibrotic activity of macrophages. Importantly, ColVI-KO mice and ColVI-KO bone marrow chimeras are protected from bleomycin-induced lung fibrosis. Therapeutic administration of a Fra-2/AP-1 inhibitor reduces ColVI expression and ameliorates fibrosis in Fra-2Tg mice and in the bleomycin model. Finally, Fra-2 and ColVI positively correlate in IPF patient samples and colocalize in lung macrophages. Therefore, the Fra-2/ColVI profibrotic axis is a promising biomarker and therapeutic target for lung fibrosis and possibly other fibrotic diseases.

Authors

Alvaro C. Ucero, Latifa Bakiri, Ben Roediger, Masakatsu Suzuki, Maria Jimenez, Pratyusha Mandal, Paola Braghetta, Paolo Bonaldo, Luis Paz-Ares, Coral Fustero-Torre, Pilar Ximenez-Embun, Ana Isabel Hernandez, Diego Megias, Erwin F. Wagner

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Figure 2

Fra-2 expression in bleomycin-induced lung fibrosis.

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Fra-2 expression in bleomycin-induced lung fibrosis. (A) Fluorescence mi...
(A) Fluorescence microscopy images of Fra-2 IF of lungs from WT mice 10 days after saline or bleomycin treatment. Nuclei are counterstained with DAPI. Arrows point to positive nuclei. Scale bars: 25 μm. (B) Time-course analysis of hydroxyproline accumulation and Fra-2 mRNA expression (qRT-PCR as Fosl2) in lungs and BALF from bleomycin-treated WT mice. ΔCt values are plotted. Sample size is n = 5 for lung tissue and n = 3 for BALF. **P < 0.01; ***P < 0.001, compared with the initial time point (0 days); 1-way ANOVA; Dunnet’s post test. (C) Confocal microscopy images on IF of fibrotic lungs from untreated and bleomycin-treated WT mice (14 days). Costaining for Fra-2 (green) and vimentin, Csf-1r, or SPC (red). Arrows point to double-positive cells. Nuclei are counterstained with DAPI (blue). Scale bars: 25 μm. (D) Flow cytometry analysis of lung GFP-expressing cells after 10 days of either saline or bleomycin (n = 3/group, from 2 independent experiments). MFI average values are presented in each plot. Arrow indicates a subpopulation of Fra-2–expressing macrophages present in bleomycin-treated mice that were absent from saline-treated controls.