Three matrix metalloproteinases are required in vivo for macrophage migration during embryonic development
Three matrix metalloproteinases are required in vivo for macrophage migration during embryonic development
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DOI：
10.1016/j.mod.2008.07.005
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发表时间：
2008-11-01
影响因子：
2.6
通讯作者：
Wheeler, Grant N.
中科院分区：
文献类型：
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作者：
Tomlinson, Matthew L.;Garcia-Morales, Carla;Wheeler, Grant N.
巨噬细胞通过其在组织重塑、伤口愈合和炎症中的作用在多种组织的发育、修复和病理学中是必不可少的。这些生物学功能也与许多人类疾病相关，例如肿瘤相关巨噬细胞在癌症进展中具有明确的功能。非洲爪蟾胚胎巨噬细胞通过直接分化从造血干细胞群体产生，并在淋巴细胞和循环系统发育之前作为宿主防御的主要机制。这种功能在小鼠和人类发育中是保守的。巨噬细胞表达许多基质金属蛋白酶（MMPs），这对其功能至关重要。MMPs是锌依赖性内切蛋白酶的大家族，在细胞外基质重塑和信号传导途径的调节中具有多种作用。我们以前已经表明MMP-7表达的爪蟾胚胎巨噬细胞。在这里，我们调查的MMP-7和其他两个MMP（MMP-18和MMP-9），也表达在迁移的巨噬细胞的作用。使用吗啉代（MO）介导的敲除的每一个基质金属蛋白酶，我们证明，它们是必要的正常的巨噬细胞在体内迁移。功能丧失效应可以使用特定的MMPs来挽救，改变为对吗啉代具有抗性，但不能通过其他MMPs的过表达来挽救。双重和三重吗啉敲除进一步表明，这些MMPs联合作用，以促进胚胎巨噬细胞迁移。因此，我们的研究结果表明，这三种MMPs具有不同的功能，它们共同对介导发育中的胚胎中的巨噬细胞迁移至关重要。这决定性地表明，MMPs是整个生物体中正常巨噬细胞迁移所必需的。(c)2008爱思唯尔爱尔兰有限公司保留所有权利。
Macrophages are essential in development, repair and pathology of a variety of tissues via their roles in tissue remodelling, wound healing and inflammation. These biological functions are also associated with a number of human diseases, for example tumour associated macrophages have well defined functions in cancer progression. Xenopus embryonic macrophages arise from a haematopoietic stem cell population by direct differentiation and act as the main mechanism of host defence, before lymphoid cells and a circulatory system have developed. This function is conserved in mouse and human development. Macrophages express a number of matrix metalloproteinases ( MMPs), which are central to their function. MMPs are a large family of zinc-dependent endoproteases with multiple roles in extracellular matrix remodelling and the modulation of signalling pathways. We have previously shown MMP-7 to be expressed by Xenopus embryonic macrophages. Here we investigate the role of MMP-7 and two other MMPs (MMP-18 and MMP-9) that are also expressed in the migrating macrophages. Using morpholino ( MO) mediated knockdown of each of the MMPs we demonstrate that they are necessary for normal macrophage migration in vivo. The loss-of-function effect can be rescued using the specific MMPs, altered to be resistant to morpholinos but not by overexpression of the other MMPs. Double and triple morpholino knockdowns further suggest that these MMPs act combinatorily to promote embryonic macrophage migration. Thus, our results imply that these three MMPs have distinct functions, which together are crucial to mediate macrophage migration in the developing embryo. This demonstrates conclusively that MMPs are required for normal macrophage cell migration in the whole organism. (c) 2008 Elsevier Ireland Ltd. All rights reserved.