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.

巨噬细胞促进成纤维细胞活化为成肌纤维细胞，成纤维细胞分泌胶原蛋白并收缩胶原蛋白基质，以急性修复受损的组织。持续的成肌纤维细胞活化导致纤维化疤痕组织的积累，损害器官功能。我们研究了将急性有益修复转变为破坏性进行性纤维化的关键过程。我们表明同型cadherin-11相互作用促进了巨噬细胞与纤维化成肌纤维细胞的特异性结合并持续活化。Cadherin-11在小鼠和人类纤维化肺组织中的巨噬细胞和成肌纤维细胞之间的接触处高度丰富。在附着测定中，钙黏着蛋白11连接介导巨噬细胞和成肌纤维细胞之间的特异性识别和强粘附。钙黏着蛋白11介导的粘附的一个功能性结果是巨噬细胞-成肌纤维细胞对之间潜伏的转化生长因子-β（TGF-β）的局部限制激活，这在巨噬细胞和成肌纤维细胞未相互接触的共培养中没有观察到。我们的数据表明，钙黏着蛋白11连接处保持彼此接近的潜在TGF-β产生巨噬细胞和TGF-β活化的成肌纤维细胞。同型cadherin-11相互作用的抑制作用可用于引起巨噬细胞-肌成纤维细胞分离，从而破坏纤维化生态位。我们的数据表明，钙黏着蛋白11连接处保持彼此接近的潜在TGF-β产生巨噬细胞和TGF-β活化的成肌纤维细胞。同型cadherin-11相互作用的抑制作用可用于引起巨噬细胞-肌成纤维细胞分离，从而破坏纤维化生态位。我们的数据表明，钙黏着蛋白11连接处保持彼此接近的潜在TGF-β产生巨噬细胞和TGF-β活化的成肌纤维细胞。同型cadherin-11相互作用的抑制作用可用于引起巨噬细胞-肌成纤维细胞分离，从而破坏纤维化生态位。