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Development of an In Vitro Assay to Evaluate Contractile Function of Mesenchymal Cells that Underwent Epithelial-Mesenchymal Transition
Published on: June 10, 2016
Macrophages programmed by apoptotic cells inhibit epithelial-mesenchymal transition in lung alveolar epithelial cells
Young-So Yoon1,2, Ye-Ji Lee1,2, Youn-Hee Choi1,2
1Department of Physiology, School of Medicine, Ewha Womans University, Seoul 158-710, Korea.
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.
Insights
Macrophages programmed by apoptotic cells inhibit TGF-β1-induced epithelial-mesenchymal transition (EMT). This macrophage programming involves cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) signaling, crucial for maintaining lung tissue homeostasis.
Area of Science:
- Cell Biology
- Immunology
- Pulmonary Medicine
Background:
- Apoptotic cell clearance is vital for tissue homeostasis, involving growth factors and signaling molecules.
- Epithelial-mesenchymal transition (EMT) is a process implicated in tissue repair and fibrosis.
Purpose of the Study:
- To investigate if macrophages conditioned by apoptotic cells can inhibit TGF-β1-induced EMT in lung alveolar epithelial cells.
- To elucidate the molecular mechanisms underlying this inhibition.
Main Methods:
- Treatment of lung alveolar epithelial cells with conditioned medium from macrophages exposed to apoptotic cells.
- Assessment of EMT markers (E-cadherin, N-cadherin, α-smooth muscle actin, transcription factors).
- Inhibition studies using cyclooxygenase (COX-2) and RhoA/Rho kinase inhibitors, and receptor antagonists (EP4, DP1, DP2, c-Met).
- In vivo studies using bleomycin-induced EMT in mouse models.
Main Results:
- Conditioned medium from apoptotic cell-exposed macrophages inhibited TGF-β1-induced EMT.
- Inhibition was reversed by COX-2 inhibitors, RhoA/Rho kinase inhibitors, and antagonists of PGE2 receptors (EP4) and c-Met.
- Apoptotic cell instillation inhibited bleomycin-induced EMT in vivo.
Conclusions:
- Macrophages programmed by apoptotic cells exert an anti-EMT effect on lung alveolar epithelial cells.
- This effect is mediated by COX-2, RhoA/Rho kinase, and prostaglandin signaling pathways.
- This represents a novel mechanism for maintaining epithelial cell homeostasis and potentially controlling fibrotic reactions.
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