Fra-2–expressing macrophages promote lung fibrosis
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
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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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 3

Fra-2 expression is essential for bleomycin-induced lung fibrosis.

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Fra-2 expression is essential for bleomycin-induced lung fibrosis. (A) S...
(A) Schematic for genetic Cre/LoxP inactivation of Fra-2 (encoded by fosl2) using intratracheal adenovirus-based Cre delivery (Fra-2ΔAd) and experimental time line. Data come from 2 independent experiments. (B) Quantification of sirius red–positive areas 14 days after bleomycin treatment. Saline-treated Fra-2ΔAd mice were used as controls. *P < 0.05, 1-way ANOVA; Bonferroni’s post test. (C) Hydroxyproline content in lungs (left lobe) 14 days after bleomycin treatment. Saline-treated Fra-2ΔAd mice were used as controls. *P < 0.05; ***P < 0.001, 1-way ANOVA; Bonferroni’s post test. (D) LR (mmHg/mL × s–1) and DC (mL/mmHg) were measured by plethysmography in the same animals over time, and mean ± SEM of the LR/DC ratios were plotted. *P < 0.05, 2-way ANOVA; Bonferroni’s post test. Statistics relative to animals receiving saline. (E) Schematic for genetic Cre/LoxP inactivation of Fra-2 (encoded by Fosl2) using the tamoxifen-inducible, lung alveolar type II cell–specific SPCCreERT2 knockin allele (Fra-2ΔAlvII*) and experimental time line. Experiment was repeated 3 times. (F) Quantification of lung sirius red–positive areas 21 days after bleomycin. *P < 0.05, unpaired 2-tailed t test. Fibrosis was assessed in 2 independent experiments. (G) Lung hydroxyproline content 21 days after bleomycin treatment. **P < 0.01, 1-way ANOVA; Bonferroni’s post test. Fibrosis was assessed in 2 independent experiments. (H) Respiratory function of bleomycin-treated Fra-2fl/fl and Fra-2ΔAlvII* mice and saline-treated Fra-2ΔAlvII* mice. *P < 0.05, 2-way ANOVA; Bonferroni’s post test. Statistics are relative to mice receiving saline.