M2 macrophages promote subconjunctival fibrosis through YAP/TAZ signalling

PurposeTo evaluate the role of M2 macrophages in subconjunctival fibrosis after silicone implantation (SI) and investigate the underlying mechanisms.Materials and methodsA model of subconjunctival fibrosis was established by SI surgery in rabbit eyes. M2 distribution and collagen deposition were evaluated by histopathology. The effects of M2 cells on the migration (using wound-scratch assay) and activation (by immunofluorescence and western blotting) of human Tenon's fibroblasts (HTFs) were investigated.ResultsThere were more M2 macrophages (CD68+/CD206+ cells) occurring in tissue samples around silicone implant at 2 weeks postoperatively. Dense collagen deposition was observed at 8 weeks after SI. In vitro experiment showed M2 expressed high level of CD206 and transforming growth factor-beta 1 (TGF-beta 1). The M2-conditioned medium promoted HTFs migration and the synthesis of collagen I and fibronectin. Meanwhile, M2-conditioned medium increased the protein levels of TGF-beta 1, TGF-beta R II, p-Smad2/3, yes-associated protein (YAP), and transcriptional coactivator with PDZ-binding motif (TAZ). Verteporfin, a YAP inhibitor, suppressedTGF-beta 1/Smad2/3-YAP/TAZ pathway and attenuated M2-induced extracellular matrix deposition by HTFs.ConclusionsTGF-beta 1/Smad2/3-YAP/TAZ signalling may be involved in M2-induced fibrotic activities in HTFs. M2 plays a key role in promoting subconjunctival fibrosis and can serve as an attractive target for anti-fibrotic therapeutics.