Cadherin-11-mediated adhesion of macrophages to myofibroblasts establishes a profibrotic niche of active TGF-β

• Published in: Science signaling Vol. 12; no. 564
• Main Authors: Lodyga, Monika, Cambridge, Elizabeth, Karvonen, Henna M, Pakshir, Pardis, Wu, Brian, Boo, Stellar, Kiebalo, Melanie, Kaarteenaho, Riitta, Glogauer, Michael, Kapoor, Mohit, Ask, Kjetil, Hinz, Boris
• Format: Journal Article
• Language: English
• Published: United States 15.01.2019
• Subjects: Animals; Cadherins - genetics; Cadherins - metabolism; Cell Adhesion; Cells, Cultured; Coculture Techniques; Fibroblasts - cytology; Fibroblasts - metabolism; Fibrosis; Humans; Macrophages - cytology; Macrophages - metabolism; Macrophages - ultrastructure; Male; Mice, Inbred C57BL; Microscopy, Electron - methods; Myofibroblasts - cytology; Myofibroblasts - metabolism; Protein Binding; RNA Interference; Signal Transduction; Transforming Growth Factor beta - metabolism
• ISSN: 1937-9145
• DOI: 10.1126/scisignal.aao3469

Macrophages contribute to the activation of fibroblastic cells into myofibroblasts, which secrete collagen and contract the collagen matrix to acutely repair injured tissue. Persistent myofibroblast activation leads to the accumulation of fibrotic scar tissue that impairs organ function. We investigated the key processes that turn acute beneficial repair into destructive progressive fibrosis. We showed that homotypic cadherin-11 interactions promoted the specific binding of macrophages to and persistent activation of profibrotic myofibroblasts. Cadherin-11 was highly abundant at contacts between macrophages and myofibroblasts in mouse and human fibrotic lung tissues. In attachment assays, cadherin-11 junctions mediated specific recognition and strong adhesion between macrophages and myofibroblasts. One functional outcome of cadherin-11-mediated adhesion was locally restricted activation of latent transforming growth factor-β (TGF-β) between macrophage-myofibroblast pairs that was not observed in cocultures of macrophages and myofibroblasts that were not in contact with one another. Our data suggest that cadherin-11 junctions maintain latent TGF-β-producing macrophages and TGF-β-activating myofibroblasts in close proximity to one another. Inhibition of homotypic cadherin-11 interactions could be used to cause macrophage-myofibroblast separation, thereby destabilizing the profibrotic niche.