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

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.

The COX‐2 inhibitor etoricoxib reduces experimental osteoarthritis and nociception in rats: The roles of TGF‐β1 and NGF expressions in chondrocytes

“…The inhibition of PGE formation by COX inhibition is the major mechanism of action of NSAIDs. PGE2 can inhibit TGF‐β‐induced mesenchymal epithelial transition (Yoon, Lee, Choi, Park, & Kang, ). PGE2 is associated with the suppressive effects of TGF‐β2 on the collagen degeneration in OA articular cartilage (Tchetina, Antoniou, Tanzer, Zukor, & Poole, ), and PGE2 can inhibit collagen degradation.…”

A STAT6 Inhibitor AS1517499 Reduces Preventive Effects of Apoptotic Cell Instillation on Bleomycin-Induced Lung Fibrosis by Suppressing PPARγ

“…Our previous studies demonstrated that anti-fibrotic effects of apoptotic cell instillation after bleomycin treatment were significant on days 14 and 21 after BLM treatment [11, 20]. In addition, anti-EMT effect of apoptotic cell instillation on primary type II alveolar epithelial cells was determined at 14 days after BLM treatment [36]. Although fibrotic response including hydroxyproline levels at 21 days after bleomycin is greater those that at 14 days, fibrotic response day 14 after bleomycin is prominent.…”

Regulation of macrophage activation by proteins expressed on apoptotic neutrophils: Subversion towards autoimmunity by proteinase 3

“…Some of the reprogramming products, such as TGFβ and arginase 1, are drivers of tissue fibrosis, while others, such as IL‐10 and 12/15‐LO metabolites limit scaring and promote restoration of normal tissue architecture and function. Intriguingly, instillation of apoptotic cells, as well as physiological neutrophil efferocytosis, seems to limit lung fibrosis by promoting macrophage reprogramming …”

“…28 Some of the reprogramming products, such as TGFβ and arginase 1, are drivers of tissue fibrosis, 27 while others, such as IL-10 29,30,31 and 12/15-LO metabolites [32][33][34] limit scaring and promote restoration of normal tissue architecture and function. Intriguingly, instillation of apoptotic cells, 35,36 as well as physiological neutrophil efferocytosis, seems to limit lung fibrosis by promoting macrophage reprogramming. 37,38 Using zymosan A-initiated peritonitis, a model of spontaneously resolving inflammation, it was shown that macrophages are reprogrammed to different phenotypes following the efferocytic uptake of apoptotic neutrophils.…”