Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.
Institute of Health and Biomedical Innovation, School of Clinical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.
Traffic. 2019 Sep;20(9):661-673. doi: 10.1111/tra.12675. Epub 2019 Jul 31.
Macrophage migration into injured or infected tissue is a key aspect in the pathophysiology of many diseases where inflammation is a driving factor. Membrane-type-1 matrix metalloproteinase (MT1-MMP) cleaves extracellular matrix components to facilitate invasion. Here we show that, unlike the constitutive MT1-MMP surface recycling seen in cancer cells, unactivated macrophages express low levels of MT1-MMP. Upon lipopolysaccharide (LPS) activation, MT1-MMP synthesis dramatically increases 10-fold at the surface by 15 hours. MT1-MMP is trafficked from the Golgi complex to the surface via late endosomes/lysosomes in a pathway regulated by the late endosome/lysosome R-SNAREs VAMP7 and VAMP8. These form two separate complexes with the surface Q-SNARE complex Stx4/SNAP23 to regulate MT1-MMP delivery to the plasma membrane. Loss of either one of these SNAREs leads to a reduction in surface MT1-MMP, gelatinase activity and reduced invasion. Thus, inhibiting MT1-MMP transport through this pathway could reduce macrophage migration and the resulting inflammation.
巨噬细胞迁移到受伤或感染的组织是许多疾病病理生理学的一个关键方面，其中炎症是一个驱动因素。膜型 1 基质金属蛋白酶（MT1-MMP）切割细胞外基质成分以促进侵袭。在这里，我们表明，与癌细胞中存在的组成型 MT1-MMP 表面再循环不同，未激活的巨噬细胞表达低水平的 MT1-MMP。在脂多糖（LPS）激活后，MT1-MMP 的合成在 15 小时内通过表面增加 10 倍。MT1-MMP 通过晚期内体/溶酶体从高尔基体复合物运送到表面，该途径受晚期内体/溶酶体 R-SNAREs VAMP7 和 VAMP8 调节。这些 SNARE 与表面 Q-SNARE 复合物 Stx4/SNAP23 形成两个独立的复合物，以调节 MT1-MMP 向质膜的传递。这些 SNARE 中的任何一个丧失都会导致表面 MT1-MMP、明胶酶活性和侵袭能力降低。因此，通过这种途径抑制 MT1-MMP 的运输可能会减少巨噬细胞的迁移和由此产生的炎症。
