Fra-2-expressing Macrophages Promote Lung Fibrosis in Mice

J Clin Invest. 2019 May 28;129(8):3293-3309. doi: 10.1172/JCI125366.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allografts
  • Animals
  • Bleomycin / adverse effects
  • Bleomycin / pharmacology
  • Bone Marrow / metabolism
  • Bone Marrow / pathology
  • Bone Marrow Transplantation
  • Collagen Type VI / biosynthesis
  • Collagen Type VI / genetics
  • Fos-Related Antigen-2 / biosynthesis*
  • Fos-Related Antigen-2 / genetics
  • Humans
  • Idiopathic Pulmonary Fibrosis / drug therapy
  • Idiopathic Pulmonary Fibrosis / genetics
  • Idiopathic Pulmonary Fibrosis / metabolism*
  • Idiopathic Pulmonary Fibrosis / pathology
  • Macrophages / immunology*
  • Macrophages / pathology
  • Mice
  • Mice, Knockout
  • Myofibroblasts / metabolism*
  • Myofibroblasts / pathology
  • Transplantation Chimera / genetics
  • Transplantation Chimera / metabolism

Substances

  • Collagen Type VI
  • FOSL2 protein, human
  • Fos-Related Antigen-2
  • Fosl2 protein, mouse
  • Bleomycin