Research ArticleFibrosis

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

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Science Signaling  15 Jan 2019:
Vol. 12, Issue 564, eaao3469
DOI: 10.1126/scisignal.aao3469

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Macrophage-myofibroblast adhesion creates a profibrotic niche

The reversible activation of fibroblasts into extracellular matrix–secreting myofibroblasts is a consequence of inflammation and is critical for wound healing and tissue repair; however, persistent myofibroblast activity causes fibrosis. Inflammatory macrophages produce transforming growth factor–β (TGF-β), a cytokine that induces the fibroblast-to-myofibroblast transition. Lodyga et al. found that the adhesion protein cadherin-11 (CDH11) was enriched at points of contact between macrophages and myofibroblasts in fibrotic lung tissues from mice and human patients. Cdh11-mediated adhesion between primary mouse macrophages and lung fibroblasts promoted the activation of fibroblasts into myofibroblasts and supported myofibroblast activity by acting as a local source of latent TGF-β that was activated by the myofibroblasts. Thus, Cdh11-mediated adhesion prolongs and targets the delivery of macrophage-produced TGF-β to myofibroblasts, creating a self-sustaining profibrotic niche.

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.

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