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 8

Fra-2 and ColVI expression in human lung fibrosis.

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Fra-2 and ColVI expression in human lung fibrosis. (A) Gene expression v...
(A) Gene expression values of COL1A2 in lungs from human patients with normal histology (normal; n = 173) and diagnosed ILD (n = 255) and COPD (n = 219). Expression values were obtained from the public gene expression database of the LGRC (GSE47460). **P < 0.01; ***P < 0.001, 1-way ANOVA; Bonferroni’s post test. (B) Gene expression values of FOSL2 (Fra-2), COL6A1 (ColVI chain α1), and COL6A3 (ColVI chain α3) genes in lungs from same cohort. Note that expression values for COL6A2 (ColVI chain α2) were absent in the data set. *P < 0.05; **P < 0.01; ***P < 0.001, 1-way ANOVA; Bonferroni’s post test. (C) Expression values for FOSL2 are plotted against COL6A3 for linear regression and Pearson’s correlation analysis of normal and ILD samples (r2 and P values are indicated). (D) Gene expression values of ColVI genes in lungs from human patients with normal histology (normal) and diagnosed IPF. Expression values were obtained from a public curated data set (GDS1252). *P < 0.05; **P < 0.01, 2-tailed paired t test. (E) Triple IHC for Fra-2 (brown-nuclear), CD68 (blue-cytoplasmic), and ColVI (purple-extracellular) of human lungs from healthy and fibrosis patients. Nuclei are counterstained with hematoxylin. Arrows point to interstitial macrophages expressing Fra-2 and colocalizing with ColVI (triple positive); arrowheads point to Fra-2–positive alveolar macrophages. Scale bars: 100 μm (low magnification); 20 μm (high magnification). (F) Working model for the role of Fra-2/ColVI in macrophages during lung fibrosis.