Chemokine receptors CCR2 and CX3CR1 regulate skin fibrosis in the mouse model of cytokine-induced systemic sclerosis
Chemokine receptors CCR2 and CX3CR1 regulate skin fibrosis in the mouse model of cytokine-induced systemic sclerosis
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DOI：
10.1016/j.jdermsci.2012.10.010
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发表时间：
2013-03-01
影响因子：
4.6
通讯作者：
Takehara, Kazuhiko
中科院分区：
文献类型：
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作者：
Arai, Minako;Ikawa, Yuka;Takehara, Kazuhiko
背景资料：皮肤纤维化病症如系统性硬化症（SSc）的特征在于细胞外基质（ECM）的过度积累，并且在某些细胞因子的影响下发展。我们先前建立了一种由外源性细胞因子诱导的皮肤纤维化小鼠模型。我们已经发现，巨噬细胞的数量和巨噬细胞趋化蛋白-1（MCP-1）mRNA的水平与皮肤纤维化的程度呈正相关。巨噬细胞可分为两个亚群，第一个表达CCR 2，第二个表达CX 3CR 1。目的：探讨以CCR 2和CX 3CR 1为基础的皮肤浸润性巨噬细胞在苦参碱诱导的小鼠皮肤纤维化模型中的作用。我们检测了野生型（WT）小鼠肉芽组织中胶原沉积的量、巨噬细胞的数量和几种mRNA的水平，结果：注射TGF-β后，WT小鼠MCP-1、Fractalkine、CCR 2和CX 3CR 1 mRNA表达增加。由TGF-β诱导的胶原蛋白的过度产生被CCR 2缺乏显著减少，而由CTGF诱导的胶原蛋白含量被恢复到野生型水平。相反，CX 3CR 1缺陷小鼠的胶原过度产生减少了近50%的TGF-β和CTGF stimulations.Conclusion：参与的CCR 2/MCP-1相互作用（CCR 2依赖环）是在TGF-β阶段。相反，Fractalkine/CX 3CR 1相互作用有助于TGF-β引发纤维化并通过CTGF维持纤维化。总的来说，两个亚群的巨噬细胞既合作又独立地在纤维化的发展中发挥重要作用。(C)2012年日本皮肤病研究学会。由Elsevier爱尔兰有限公司出版。保留所有权利。
Background: Skin fibrotic disorders such as systemic sclerosis (SSc) are characterized by an excessive accumulation of extracellular matrix (ECM), and develop under the influence of certain cytokines. We previously established a mouse model of skin fibrosis induced by exogenous application of cytokines. We have revealed that both the number of macrophages and the levels of macrophage chemoattractant protein-1 (MCP-1) mRNA positively correlate with the extent of skin fibrosis. Macrophages can be divided into two subsets, the first expressing CCR2, and the second expressing CX3CR1.Objective: To elucidate the role of skin infiltrating macrophages based on CCR2 and CX3CR1 in this cytokine-induced murine fibrosis model.Methods: We examined the amounts of collagen deposited in granulation tissues, the numbers of macrophages and the levels of several mRNA in wild type (WT) mice, CCR2(-/-) mice, and CX3CR1(-/-) mice during injections of transforming growth factor-beta (TGF-beta) followed by injections of connective tissue growth factor (CTGF).Results: TGF-beta injection increased the expressions of MCP-1, fractalkine, CCR2 and CX3CR1 mRNA in WT mice. The overproduction of collagen induced by TGF-beta was significantly reduced by CCR2 deficiency, while collagen contents induced by CTGF were restored to wild-type levels. In contrast, overproduction of collagen in CX3CR1-deficient mice decreased nearly 50% by both TGF-beta and CTGF stimulations.Conclusion: The involvement of CCR2/MCP-1 interaction (CCR2-dependent loop) was during the TGF-beta phase. In contrast, the fractalkine/CX3CR1 interaction contributes to the initiation of fibrosis by TGF-beta and its maintenance by CTGF. Collectively, two subsets of macrophages both cooperatively and independently play important roles in the development of fibrosis. (C) 2012 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.