Macrophage elastase kills bacteria within murine macrophages

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Abstract
Normal physiologic roles for many of the matrix metalloproteinases (MMPs), an extensive family of zinc-dependent endopeptidases, remain poorly understood. Matrix metalloproteinase-12 (MMP-12, also known as macrophage elastase) is now shown to possess direct antimicrobial activity against Gram-positive and Gram-negative bacteria. This function of MMP-12 is associated with the carboxy-terminal domain of the molecule, rather than its catalytic site. And surprisingly — since MMPs are in the main active within the extracellular space — its antimicrobial activity is exerted within the cell. This work also highlights a role for macrophages in the earliest stages of acute bacterial infection, more familiarly regarded as the province of neutrophils. Macrophages possess several substances with which they can kill bacteria, including reactive oxygen species, nitric oxide, and antimicrobial proteins. Here, macrophage elastase, an enzyme implicated in several disease processes including emphysema, is shown to have direct antimicrobial activity against Gram-positive and Gram-negative bacteria. Macrophages are aptly positioned to function as the primary line of defence against invading pathogens in many organs, including the lung and peritoneum. Their ability to phagocytose and clear microorganisms has been well documented1,2. Macrophages possess several substances with which they can kill bacteria, including reactive oxygen species, nitric oxide, and antimicrobial proteins3,4,5,6,7,8,9. We proposed that macrophage-derived proteinases may contribute to the antimicrobial properties of macrophages. Macrophage elastase (also known as matrix metalloproteinase 12 or MMP12) is an enzyme predominantly expressed in mature tissue macrophages10 and is implicated in several disease processes, including emphysema11. Physiological functions for MMP12 have not been described. Here we show that Mmp12-/- mice exhibit impaired bacterial clearance and increased mortality when challenged with both Gram-negative and Gram-positive bacteria at macrophage-rich portals of entry, such as the peritoneum and lung. Intracellular stores of MMP12 are mobilized to macrophage phagolysosomes after the ingestion of bacterial pathogens. Once inside phagolysosomes, MMP12 adheres to bacterial cell walls where it disrupts cellular membranes resulting in bacterial death. The antimicrobial properties of MMP12 do not reside within its catalytic domain, but rather within the carboxy-terminal domain. This domain contains a unique four amino acid sequence on an exposed β loop of the protein that is required for the observed antimicrobial activity. The present study represents, to our knowledge, the first report of direct antimicrobial activity by a matrix metallopeptidase, and describes a new antimicrobial peptide that is sequentially and structurally unique in nature.