Department of Evolutionary Immunobiology, Institute of Zoology, Jagiellonian University, ul. Ingardena 6, PL-30-060 Krakow, Poland.
Immunol Lett. 2009 Sep 22;126(1-2):73-82. doi: 10.1016/j.imlet.2009.08.002. Epub 2009 Aug 12.
Matrix metalloproteinase 9 (MMP-9) is a Zn(2+)-dependent endopeptidase that degrades some of the components of basement membranes and extracellular matrix and thus participates in leukocyte infiltration during inflammation. In a model of zymosan peritonitis, neutrophil infiltration in MMP-deficient (MMP-9(-/-)) mice was significantly weaker at the time of their maximal influx in wild-type mice (6h). However, during the late stages of peritonitis (24h) an extended accumulation of neutrophils was observed in MMP-9(-/-)versus the wild-type mice. Recently, we reported that the ratio of apoptosis of inflammatory leukocytes is impaired in MMP-9(-/-) mice during late peritonitis and the process depends on COX-1-driven PGE(2). Here we scrutinized the alterations in apoptotic mechanisms by comparisons between MMP-9(-/-) and the wild-type mice. Altered apoptosis occurred only during late (24h) peritonitis and concerned only neutrophils, and not macrophages, mast cells or lymphocytes. Furthermore, expression and activity of caspases was altered in MMP-9(-/-) animals, delayed for caspase-8 and -9, and decreased in the case of caspase-3. Also the expression of Bax/Bcl-2 proteins was changed in MMP-9(-/-) mice. These changes, and in particular the impaired neutrophil apoptosis and weaker caspase-3 activity, were restored by the selective COX-1 inhibition. We conclude that in mice lacking MMP-9 the enhanced COX-1-PGE(2) decreases caspase-3 expression and activity leading to impaired apoptosis of inflammatory neutrophils resulting in abnormal accumulation of the cells at the inflammatory focus. The data also reinforce the notion that MMP-9 is a key enzyme in neutrophil biology.
基质金属蛋白酶 9（MMP-9）是一种锌依赖性内肽酶，可降解基底膜和细胞外基质的某些成分，因此参与炎症期间的白细胞浸润。在酵母聚糖性腹膜炎模型中，MMP 缺陷型（MMP-9(-/-)）小鼠中性粒细胞的浸润在野生型小鼠最大浸润时明显较弱（6 小时）。然而，在腹膜炎的晚期（24 小时），与野生型小鼠相比，MMP-9(-/-)小鼠中中性粒细胞的积累时间延长。最近，我们报道 MMP-9(-/-)小鼠在晚期腹膜炎期间炎症白细胞凋亡的比例受损，并且该过程依赖 COX-1 驱动的 PGE(2)。在这里，我们通过 MMP-9(-/-)和野生型小鼠之间的比较来研究凋亡机制的改变。只有在晚期（24 小时）腹膜炎时才会发生改变的凋亡，并且仅涉及中性粒细胞，而不涉及巨噬细胞、肥大细胞或淋巴细胞。此外，MMP-9(-/-)动物中的 caspase 表达和活性发生改变，caspase-8 和 -9 延迟，caspase-3 减少。Bax/Bcl-2 蛋白的表达在 MMP-9(-/-)小鼠中也发生改变。这些变化，特别是中性粒细胞凋亡受损和 caspase-3 活性减弱，通过选择性 COX-1 抑制得到恢复。我们得出结论，在缺乏 MMP-9 的小鼠中，增强的 COX-1-PGE(2)降低了 caspase-3 的表达和活性，导致炎症性中性粒细胞凋亡受损，导致细胞在炎症焦点处异常积聚。这些数据还加强了 MMP-9 是中性粒细胞生物学的关键酶的观点。
