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Epilysin (MMP-28) Restrains Early Macrophage Recruitment in Pseudomonas aeruginosa Pneumonia¹

Anne M. Manicone^2,*,, Timothy P. Birkland^*,, Michelle Lin^*,, Tomoko Betsuyaku, Nico van Rooijen, Jouko Lohi^¶, Jorma Keski-Oja^¶, Ying Wang^*,, Shawn J. Skerrett and William C. Parks^*,

^* Center for Lung Biology and Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA 98109; First Department of Medicine, Hokkaido University, Sapporo, Japan; Department of Cell Biology, Faculty of Medicine, Free University, Amsterdam, The Netherlands; and ^¶ Department of Pathology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants HL077555 and HL084385 and by the Academy of Finland and Helsinki University Hospital.

² Address correspondence and reprint requests to Dr. Anne M. Manicone, Center for Lung Biology, University of Washington, 815 Mercer Street, Seattle, WA 98109. E-mail address: manicone{at}u.washington.edu

³ Abbreviations used in this paper: MMP, matrix metalloproteinase; BALF, bronchoalveolar lavage fluid; BMDM, bone marrow-derived macrophage; CCSP, Clara cell secretory protein; ES, embryonic stem; LCM, laser capture microdissection; qRT-PCR, quantitative RT-PCR; WT, wild type.