Fra-2–expressing macrophages promote lung fibrosis

Fra-2–expressing macrophages promote lung fibrosis.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1172/JCI125366
Journal or Publication Title: Journal of Clinical Investigation
Volume: 129
Number: 8
Page Range: pp. 3293-3309
Date: 2019
Divisions: Immune Imaging
Depositing User: General Admin
Identification Number: 10.1172/JCI125366
ISSN: 0021-9738
Date Deposited: 21 Dec 2020 23:07
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 up-regulated in three 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 pro-fibrotic activity of macrophages. Importantly, ColVI knock-out mice (KO) 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 co-localize in lung macrophages. Therefore, the Fra-2/ColVI pro-fibrotic axis is a promising biomarker and therapeutic target for lung fibrosis, and possibly other fibrotic diseases.

Keywords: Collagens; Fibrosis; Inflammation; Macrophages; Pulmonology.

Creators:
Creators
Email
Ucero, Alvaro C.
UNSPECIFIED
Bakiri, Latifa
UNSPECIFIED
Roediger, Ben
UNSPECIFIED
Suzuki, Masakatsu
UNSPECIFIED
Jimenez, Maria
UNSPECIFIED
Mandal, Pratyusha
UNSPECIFIED
Braghetta, Paola
UNSPECIFIED
Bonaldo, Paolo
UNSPECIFIED
Paz-Ares, Luis
UNSPECIFIED
Fustero-Torre, Coral
UNSPECIFIED
Ximenez-Embun, Pilar
UNSPECIFIED
Hernandez, Ana Isabel
UNSPECIFIED
Megias, Diego
UNSPECIFIED
Wagner, Erwin F.
UNSPECIFIED
Last Modified: 21 Dec 2020 23:07
URI: https://eprints.centenary.org.au/id/eprint/170

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