Three-dimensional migration of macrophages requires Hck for podosome organization and extracellular matrix proteolysis
Three-dimensional migration of macrophages requires Hck for podosome organization and extracellular matrix proteolysis
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DOI：
10.1182/blood-2009-04-218735
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发表时间：
2010-02-18
期刊：
影响因子：
20.3
通讯作者：
Maridonneau-Parini, Isabelle
中科院分区：
文献类型：
--
作者：
Cougoule, Celine;Le Cabec, Veronique;Maridonneau-Parini, Isabelle
吞噬细胞的组织渗透加剧了几种人类的病理，包括慢性炎症或癌症。然而，巨噬细胞通过间质组织迁移的机制还知之甚少。我们研究了HCK的作用，这是一种参与基质黏附和降解结构组织的Src家族激酶，称为足体。在发生腹膜炎的HCK(-/-)小鼠中，我们发现巨噬细胞聚集在间质组织中，几乎到达腹膜腔。在体外，HCK(-/-)骨髓巨噬细胞(BMDM)的3维(3D)迁移和基质降解能力(2种依赖于蛋白酶的特性)受到影响。这些巨噬细胞形成很少且尺寸较小的足体花环，因此，尽管基质金属蛋白酶正常表达和活性，但其下方的基质蛋白分解作用减弱。最后，在不能渗透基质的成纤维细胞中，异位表达的HCK提供了3D迁移增益功能，这与足体花环的形成呈正相关。综上所述，足体的大花环状空间组织、细胞外基质的蛋白降解和3D迁移似乎在功能上与巨噬细胞内的HCK相关并受其调控。作为第一个结合吞噬细胞限制性表达和3D迁移作用的蛋白质，HCK可能成为新的抗炎和抗肿瘤分子的靶点。(血。2010；115：1444-1452)
Tissue infiltration of phagocytes exacerbates several human pathologies including chronic inflammations or cancers. However, the mechanisms involved in macrophage migration through interstitial tissues are poorly understood. We investigated the role of Hck, a Src-family kinase involved in the organization of matrix adhesion and degradation structures called podosomes. In Hck(-/-) mice submitted to peritonitis, we found that macrophages accumulated in interstitial tissues and barely reached the peritoneal cavity. In vitro, 3-dimensional (3D) migration and matrix degradation abilities, 2 protease-dependent properties of bone marrow-derived macrophages (BMDMs), were affected in Hck(-/-) BMDMs. These macrophages formed few and undersized podosome rosettes and, consequently, had reduced matrix proteolysis operating underneath despite normal expression and activity of matrix metalloproteases. Finally, in fibroblasts unable to infiltrate matrix, ectopic expression of Hck provided the gain-of-3D migration function, which correlated positively with formation of podosome rosettes. In conclusion, spatial organization of podosomes as large rosettes, proteolytic degradation of extracellular matrix, and 3D migration appeared to be functionally linked and regulated by Hck in macrophages. Hck, as the first protein combining a phagocyte-limited expression with a role in 3D migration, could be a target for new anti-inflammatory and antitumor molecules. (Blood. 2010; 115: 1444-1452)