Epilysin (MMP-28) restrains early macrophage recruitment in Pseudomonas aeruginosa pneumonia.
Epilysin (MMP-28) restrains early macrophage recruitment in Pseudomonas aeruginosa pneumonia.
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DOI：
10.4049/jimmunol.0713949
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发表时间：
2009-03-15
期刊：
影响因子：
--
通讯作者：
Parks WC
中科院分区：
文献类型：
--
作者：
Manicone AM;Birkland TP;Lin M;Betsuyaku T;van Rooijen N;Lohi J;Keski-Oja J;Wang Y;Skerrett SJ;Parks WC
基质金属蛋白酶家族中的几个成员在天然免疫的各种过程中发挥作用，特别是在控制白细胞内流方面。黏附素(MMP28)在多种组织中表达，在成年小鼠肺中表达最高，在肺上皮细胞(Clara细胞)中表达。骨髓来源的巨噬细胞也表达黏附素，而肺泡巨噬细胞则不表达，提示其在巨噬细胞中的表达依赖于其定位和分化。为了评估这种基质金属蛋白酶的作用，我们产生了Eepysin缺失(MMP28−/−)小鼠。尽管Eepysin在正常组织中有结构性表达，但MMP28−/−小鼠没有明显的表型。然而，使用铜绿假单胞菌肺炎的小鼠模型，我们发现MMP28−/−小鼠早期肺内巨噬细胞募集增加，细菌清除增强，肺中性粒细胞减少，我们预测这是由于巨噬细胞加速涌入。野生型和MMP28−/−小鼠的巨噬细胞耗尽证实了巨噬细胞在清除铜绿假单胞菌和调节中性粒细胞募集方面的作用。此外，我们观察到来自MMP28−/−小鼠的巨噬细胞比野生型细胞更快地迁移到铜绿假单胞菌治疗的两种基因型的小鼠的支气管肺泡灌洗液中。这些观察表明，Eepysin通过抑制巨噬细胞的趋化作用，发挥了巨噬细胞募集的内在负性调节作用。
Several members of the matrix metalloproteinase (MMP) family function in various processes of innate immunity, particularly in controlling leukocyte influx. Epilysin (MMP-28) is expressed in numerous tissues, and in adult mice, it has the highest expression in lung, where it is detected in bronchial epithelial cells (Clara cells). Epilysin is also expressed by bone-marrow derived macrophages, but not by alveolar macrophages, suggesting that its expression by macrophages is dependent on localization and differentiation. To assess the role of this MMP, we generated epilysin-null (Mmp28−/−) mice. Although epilysin is constitutively expressed in normal tissues, Mmp28−/− mice have no overt phenotype. However, using a murine model of Pseudomonas aeruginosa pneumonia, we found that Mmp28−/− mice had an early increase in macrophage recruitment into the lungs, as well as enhanced bacterial clearance and reduced pulmonary neutrophilia, which we predict were due to accelerated macrophage influx. Macrophage depletion in wildtype and Mmp28−/− mice confirmed a role for macrophages in clearing P. aeruginosa and regulating neutrophil recruitment. Furthermore, we observed that macrophages derived from Mmp28−/− mice migrated faster than wildtype cells to bronchoalveolar lavage from P. aeruginosa-treated mice of either genotype. These observations indicate that epilysin functions as an intrinsic negative regulator of macrophage recruitment by retarding the chemotaxis of these cells.
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3.1
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