Format

Send to

Choose Destination
Sci Signal. 2019 Jan 15;12(564). pii: eaao3469. doi: 10.1126/scisignal.aao3469.

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

Author information

1
Laboratory of Tissue Repair and Regeneration, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5G 1G6, Canada.
2
Respiratory Medicine, Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, POB 20, 90029, Oulu, Finland.
3
Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario M5S 3G9, Canada.
4
Department of Surgery and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5T 2S8, Canada.
5
Arthritis Program, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.
6
Faculty of Dentistry, University of Toronto, Toronto, Ontario M5G 1G6, Canada.
7
Department of Medicine, McMaster University, Firestone Institute for Respiratory Health, Hamilton, Ontario L8N 4A6, Canada.
8
Laboratory of Tissue Repair and Regeneration, Faculty of Dentistry, University of Toronto, Toronto, Ontario M5G 1G6, Canada. boris.hinz@utoronto.ca.

Abstract

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.

PMID:
30647145
DOI:
10.1126/scisignal.aao3469

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center