2026-06-01T02:48:00Zhttps://docta.ucm.es/rest/oai/request

oai:docta.ucm.es:20.500.14352/1331992026-02-26T01:07:08Zcom_20.500.14352_14col_20.500.14352_15

Fra-2–expressing macrophages promote lung fibrosis Ucero Herrería, Álvaro Conrado Wagner, Erwin F. 612 Fra-2/AP-1 Macrophages Lung fibrosis Collagen VI Fisiología Inmunología Neumología 2411 Fisiología Humana 3207.10 Inmunopatología 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. Depto. de Fisiología Fac. de Medicina TRUE pub 2026-02-25T12:39:06Z 2026-02-25T12:39:06Z 2019-05-28 journal article VoR https://hdl.handle.net/20.500.14352/133199 0021-9738 10.1172/JCI125366 1558-8238 eng 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. restricted access application/pdf American Society for Clinical Investigation