Letter | Published:

Macrophage elastase kills bacteria within murine macrophages

Nature volume 460, pages 637641 (30 July 2009) | Download Citation

Abstract

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.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (NIH) National Heart, Lung and Blood Institute (NHLBI) (S.D.S.) and Spanish and European public agencies (F.X.G.-R.).

Author Contributions A.M.H. performed in vivo and in vitro studies, contributed to data interpretation and mechanistic advance, prepared the manuscript and figures, and performed all revisions. W.O.H. performed in vivo and in vitro studies and contributed to study design, data analysis, and mechanistic advance. C.S.R. performed CTD processing studies. F.X.G.-R. constructed the three-dimensional homology model of MMP12 CTD. S.D.S. generated Mmp12-/- mice and all recombinant proteins, was responsible for study design, data interpretation, and mechanistic advance, and assisted with manuscript preparation.

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Author notes

    • A. McGarry Houghton
    •  & William O. Hartzell

    These authors contributed equally to this work.

Affiliations

  1. Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA

    • A. McGarry Houghton
    • , Clinton S. Robbins
    •  & Steven D. Shapiro
  2. Division of Pulmonary and Critical Care, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA

    • William O. Hartzell
  3. Proteolysis Lab, Molecular Biology Institute of Barcelona (CSIC), Barcelona Science Park, Helix Building, c/ Baldiri Reixac 15-21, 08028 Barcelona, Spain

    • F. Xavier Gomis-Rüth

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Correspondence to A. McGarry Houghton.

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https://doi.org/10.1038/nature08181

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