Manicone Anne M, Birkland Timothy P, Lin Michelle, Betsuyaku Tomoko, van Rooijen Nico, Lohi Jouko, Keski-Oja Jorma, Wang Ying, Skerrett Shawn J, Parks William C
Division of Pulmonary and Critical Care Medicine, Center for Lung Biology, University of Washington, Seattle, WA 98109, USA.
J Immunol. 2009 Mar 15;182(6):3866-76. doi: 10.4049/jimmunol.0713949.
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 predicted were due to accelerated macrophage influx. Macrophage depletion in WT 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 did wild-type cells to bronchoalveolar lavage fluid 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.
基质金属蛋白酶（MMP）家族的多个成员在天然免疫的各种过程中发挥作用，尤其是在控制白细胞流入方面。表皮溶解素（MMP-28）在多种组织中表达，在成年小鼠中，它在肺中的表达最高，在支气管上皮细胞（克拉拉细胞）中可检测到。表皮溶解素也由骨髓来源的巨噬细胞表达，但不由肺泡巨噬细胞表达，这表明巨噬细胞对其表达取决于定位和分化。为了评估这种MMP的作用，我们构建了表皮溶解素基因敲除（Mmp28(-/-)）小鼠。尽管表皮溶解素在正常组织中组成性表达，但Mmp28(-/-)小鼠没有明显的表型。然而，使用铜绿假单胞菌肺炎小鼠模型，我们发现Mmp28(-/-)小鼠肺部巨噬细胞募集早期增加，细菌清除增强，肺部中性粒细胞浸润减少，我们推测这是由于巨噬细胞流入加速所致。野生型和Mmp28(-/-)小鼠中的巨噬细胞耗竭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中的作用。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来自两种基因型铜绿假单胞菌处理小鼠的支气管肺泡灌洗液中。这些观察结果表明，表皮溶解素通过延缓这些细胞的趋化作用，作为巨噬细胞募集的内在负调节因子发挥作用。
