[HTML][HTML] Fra-2–expressing macrophages promote lung fibrosis

AC Ucero, L Bakiri, B Roediger… - The Journal of …, 2019 - Am Soc Clin Investig
AC Ucero, L Bakiri, B Roediger, M Suzuki, M Jimenez, P Mandal, P Braghetta, P Bonaldo
The Journal of clinical investigation, 2019Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation