RT Journal Article
T1 Fra-2–expressing macrophages promote lung fibrosis
A1 Ucero Herrería, Álvaro Conrado
A1 Wagner, Erwin F.
AB 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.
PB American Society for Clinical Investigation
SN 0021-9738
YR 2019
FD 2019-05-28
LK https://hdl.handle.net/20.500.14352/133199
UL https://hdl.handle.net/20.500.14352/133199
LA eng
NO Ucero AC, Bakiri L, Roediger B, Suzuki M, Jimenez M, Mandal P, Braghetta P, Bonaldo P, Paz-Ares L, Fustero-Torre C, Ximenez-Embun P, Hernandez AI, Megias D, Wagner EF. Fra-2–expressing macrophages promote lung fibrosis. Journal of Clinical Investigation. 2019;129(8): 2/JCI125366. PMID: 31135379.
DS Docta Complutense
RD 18 mar 2026