Macrophages programmed by apoptotic cells inhibit epithelial-mesenchymal transition in lung alveolar epithelial cells via PGE2, PGD2, and HGF

Sci Rep. 2016 Feb 15:6:20992. doi: 10.1038/srep20992.

Abstract

Apoptotic cell clearance results in the release of growth factors and the action of signaling molecules involved in tissue homeostasis maintenance. Here, we investigated whether and how macrophages programmed by apoptotic cells inhibit the TGF-β1-induced Epithelial-mesenchymal transition (EMT) process in lung alveolar epithelial cells. Treatment with conditioned medium derived from macrophages exposed to apoptotic cells, but not viable or necrotic cells, inhibited TGF-β1-induced EMT, including loss of E-cadherin, synthesis of N-cadherin and α-smooth muscle actin, and induction of EMT-activating transcription factors, such as Snail1/2, Zeb1/2, and Twist1. Exposure of macrophages to cyclooxygenase (COX-2) inhibitors (NS-398 and COX-2 siRNA) or RhoA/Rho kinase inhibitors (Y-27632 and RhoA siRNA) and LA-4 cells to antagonists of prostaglandin E2 (PGE2) receptor (EP4 [AH-23848]), PGD2 receptors (DP1 [BW-A868C] and DP2 [BAY-u3405]), or the hepatocyte growth factor (HGF) receptor c-Met (PHA-665752), reversed EMT inhibition by the conditioned medium. Additionally, we found that apoptotic cell instillation inhibited bleomycin-mediated EMT in primary mouse alveolar type II epithelial cells in vivo. Our data suggest a new model for epithelial cell homeostasis, by which the anti-EMT programming of macrophages by apoptotic cells may control the progressive fibrotic reaction via the production of potent paracrine EMT inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alveolar Epithelial Cells / drug effects*
  • Alveolar Epithelial Cells / metabolism
  • Amides / administration & dosage
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics*
  • Culture Media, Conditioned / pharmacology
  • Cyclooxygenase 2 / metabolism
  • Cyclooxygenase 2 Inhibitors / administration & dosage
  • Dinoprostone / antagonists & inhibitors
  • Dinoprostone / biosynthesis*
  • Dinoprostone / genetics
  • Epithelial-Mesenchymal Transition / drug effects
  • Epithelial-Mesenchymal Transition / genetics
  • Gene Expression Regulation / drug effects
  • Hepatocyte Growth Factor / antagonists & inhibitors
  • Hepatocyte Growth Factor / biosynthesis*
  • Hepatocyte Growth Factor / genetics
  • Macrophages / metabolism
  • Mice
  • Nitrobenzenes / administration & dosage
  • Prostaglandin D2 / antagonists & inhibitors
  • Prostaglandin D2 / biosynthesis*
  • Prostaglandin D2 / genetics
  • Pyridines / administration & dosage
  • Sulfonamides / administration & dosage
  • rho GTP-Binding Proteins / antagonists & inhibitors
  • rho GTP-Binding Proteins / genetics
  • rhoA GTP-Binding Protein

Substances

  • Amides
  • Culture Media, Conditioned
  • Cyclooxygenase 2 Inhibitors
  • HGF protein, mouse
  • Nitrobenzenes
  • Pyridines
  • Sulfonamides
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • Y 27632
  • Hepatocyte Growth Factor
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • RhoA protein, mouse
  • rho GTP-Binding Proteins
  • rhoA GTP-Binding Protein
  • Dinoprostone
  • Prostaglandin D2