Rac2 is required for alternative macrophage activation and bleomycin induced pulmonary fibrosis; a macrophage autonomous phenotype

PLoS One. 2017 Aug 17;12(8):e0182851. doi: 10.1371/journal.pone.0182851. eCollection 2017.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by cellular phenotype alterations and deposition of extracellular matrix proteins. The alternative activation of macrophages in the lungs has been associated as a major factor promoting pulmonary fibrosis, however the mechanisms underlying this phenomenon are poorly understood. In the present study, we have defined a molecular mechanism by which signals transmitted from the extracellular matrix via the α4β1 integrin lead to the activation of Rac2 which regulates alternative macrophage differentiation, a signaling axis within the pulmonary macrophage compartment required for bleomycin induced pulmonary fibrosis. Mice deficient in Rac2 were protected against bleomycin-induced fibrosis and displayed diminished collagen deposition in association with lower expression of alternatively activated profibrotic macrophage markers. We have demonstrated a macrophage autonomous process by which the injection of M2 and not M1 macrophages restored the bleomycin induced pulmonary fibrosis susceptibility in Rac2-/- mice, establishing a critical role for a macrophage Rac2 signaling axis in the regulation of macrophage differentiation and lung fibrosis in vivo. We also demonstrate that markers of alternative macrophage activation are increased in patients with IPF. Taken together, these studies define an important role for an integrin-driven Rac2 signaling axis in macrophages, and reveal that Rac2 activation is required for polarization of macrophages towards a profibrotic phenotype and progression of pulmonary fibrosis in vivo.

MeSH terms

  • Animals
  • Bleomycin / toxicity
  • Cells, Cultured
  • Collagen / metabolism
  • Humans
  • Idiopathic Pulmonary Fibrosis / etiology
  • Idiopathic Pulmonary Fibrosis / genetics
  • Idiopathic Pulmonary Fibrosis / immunology*
  • Macrophage Activation*
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Phenotype
  • rac GTP-Binding Proteins / genetics*
  • rac GTP-Binding Proteins / metabolism

Substances

  • Bleomycin
  • Collagen
  • rac2 GTP-binding protein
  • rac GTP-Binding Proteins