Interleukin-4 Receptor α Signaling in Myeloid Cells Controls Collagen Fibril Assembly in Skin Repair.
Interleukin-4 Receptor α Signaling in Myeloid Cells Controls Collagen Fibril Assembly in Skin Repair.
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DOI：
10.1016/j.immuni.2015.09.005
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发表时间：
2015-10-20
期刊：
影响因子：
32.4
通讯作者：
Eming SA
中科院分区：
文献类型：
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作者：
Knipper JA;Willenborg S;Brinckmann J;Bloch W;Maaß T;Wagener R;Krieg T;Sutherland T;Munitz A;Rothenberg ME;Niehoff A;Richardson R;Hammerschmidt M;Allen JE;Eming SA
损伤过程中免疫反应的激活是一个关键的早期事件，它决定了组织修复的结果是再生还是用疤痕取代受损组织。免疫信号控制这些根本不同的再生途径的机制在很大程度上尚不清楚。我们已经证明，在小鼠皮肤修复过程中，白介素4受体α(IL-4Rα)依赖的巨噬细胞激活控制着胶原纤维的组装，这一过程对于有效的修复是重要的，同时具有不利的促纤维化作用。我们发现Relm-α是巨噬细胞中IL-4Rα信号转导到成纤维细胞中赖氨酰羟基酶2(LH2)诱导过程中的一个重要角色，LH2是一种引导持续性促纤维化胶原交联酶。值得注意的是，Remm-β诱导了人成纤维细胞中的LH2，在脂肪皮肤病(一种过度的人类皮肤纤维化)中，这两种因子的表达都增加了。总而言之，我们的发现为2型免疫和促纤维化途径的启动之间的联系提供了机械性的见解。
Activation of the immune response during injury is a critical early event that determines whether the outcome of tissue restoration is regeneration or replacement of the damaged tissue with a scar. The mechanisms by which immune signals control these fundamentally different regenerative pathways are largely unknown. We have demonstrated that, during skin repair in mice, interleukin-4 receptor α (IL-4Rα)-dependent macrophage activation controlled collagen fibril assembly and that this process was important for effective repair while having adverse pro-fibrotic effects. We identified Relm-α as one important player in the pathway from IL-4Rα signaling in macrophages to the induction of lysyl hydroxylase 2 (LH2), an enzyme that directs persistent pro-fibrotic collagen cross-links, in fibroblasts. Notably, Relm-β induced LH2 in human fibroblasts, and expression of both factors was increased in lipodermatosclerosis, a condition of excessive human skin fibrosis. Collectively, our findings provide mechanistic insights into the link between type 2 immunity and initiation of pro-fibrotic pathways.