Peters Thorsten, Sindrilaru Anca, Hinz Boris, Hinrichs Ralf, Menke André, Al-Azzeh Ezz Al Din, Holzwarth Katrin, Oreshkova Tsvetelina, Wang Honglin, Kess Daniel, Walzog Barbara, Sulyok Silke, Sunderkötter Cord, Friedrich Wilhelm, Wlaschek Meinhard, Krieg Thomas, Scharffetter-Kochanek Karin
Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany.
EMBO J. 2005 Oct 5;24(19):3400-10. doi: 10.1038/sj.emboj.7600809. Epub 2005 Sep 8.
We studied the mechanisms underlying the severely impaired wound healing associated with human leukocyte-adhesion deficiency syndrome-1 (LAD1) using a murine disease model. In CD18(-/-) mice, healing of full-thickness wounds was severely delayed during granulation-tissue contraction, a phase where myofibroblasts play a major role. Interestingly, expression levels of myofibroblast markers alpha-smooth muscle actin and ED-A fibronectin were substantially reduced in wounds of CD18(-/-) mice, suggesting an impaired myofibroblast differentiation. TGF-beta signalling was clearly involved since TGF-beta1 and TGF-beta receptor type-II protein levels were decreased, while TGF-beta(1) injections into wound margins fully re-established wound closure. Since, in CD18(-/-) mice, defective migration leads to a severe reduction of neutrophils in wounds, infiltrating macrophages might not phagocytose apoptotic CD18(-/-) neutrophils. Macrophages would thus be lacking their main stimulus to secrete TGF-beta1. Indeed, in neutrophil-macrophage cocultures, lack of CD18 on either cell type leads to dramatically reduced TGF-beta1 release by macrophages due to defective adhesion to, and subsequent impaired phagocytic clearance of, neutrophils. Our data demonstrates that the paracrine secretion of growth factors is essential for cellular differentiation in wound healing.
我们使用小鼠疾病模型研究了与人类白细胞黏附缺陷综合征1型（LAD1）相关的严重受损伤口愈合的潜在机制。在CD18基因敲除（-/-）小鼠中，全层伤口在肉芽组织收缩阶段愈合严重延迟，而在这个阶段肌成纤维细胞起主要作用。有趣的是，CD18基因敲除（-/-）小鼠伤口中肌成纤维细胞标志物α-平滑肌肌动蛋白和ED-A纤连蛋白的表达水平大幅降低，提示肌成纤维细胞分化受损。TGF-β信号通路明显参与其中，因为TGF-β1和II型TGF-β受体蛋白水平降低，而向伤口边缘注射TGF-β1可完全恢复伤口闭合。由于在CD18基因敲除（-/-）小鼠中，迁移缺陷导致伤口中嗜中性粒细胞严重减少，浸润的巨噬细胞可能无法吞噬凋亡的CD18基因敲除（-/-）嗜中性粒细胞。因此，巨噬细胞将缺乏分泌TGF-β1的主要刺激。事实上，在嗜中性粒细胞-巨噬细胞共培养中，任何一种细胞类型上缺乏CD18都会导致巨噬细胞分泌TGF-β1显著减少，这是由于与嗜中性粒细胞的黏附缺陷以及随后吞噬清除功能受损所致。我们的数据表明，生长因子的旁分泌分泌对于伤口愈合中的细胞分化至关重要。
