Metalloelastase is required for macrophage-mediated proteolysis and matrix invasion in mice.

Abstract

Macrophages secrete a variety of proteinases that are thought to participate in remodeling of the extracellular matrix associated with inflammatory processes. We have eliminated expression of the macrophage metalloelastase (MME) gene by targeted disruption to assess the role of this protein in macrophage-mediated proteolysis. We found that the macrophages of MME-deficient (MME -/-) mice have a markedly diminished capacity to degrade extracellular matrix components. In addition, MME -/-macrophages are essentially unable to penetrate reconstituted basement membranes in vitro and in vivo. MME is therefore required for macrophage-mediated extracellular matrix proteolysis and tissue invasion.Macrophages produce a variety of cysteine, serine, and metalloproteinases that are involved with the physiologic tissue remodeling associated with inflammation and wound repair. However, proteolytic activity released by macrophages can also lead to pathologic tissue destruction. Metalloproteinases constitute a family of structurally related matrix-degrading proteinases including the collagenases, stromelysins, gelatinases, matrilysin, membrane-type metalloproteinases, and macrophage metalloelastase. These enzymes require zinc for catalytic activity and are inhibited by the tissue inhibitors of metalloproteinases (1, 2). Macrophage metalloelastase (MME) is characterized by macrophage-specific expression and the capacity to hydrolyze a broad spectrum of substrates (3,4). To determine the contribution of metalloelastase to macrophage-mediated proteolysis, we generated mice deficient in metalloelastase (MME -/-) by targeted mutagenesis. MATERIALS AND METHODSGeneration of the Targeting Construct. A genomic clone encoding MME was isolated from a mouse 129/SvJ library (Stratagene) by using the cDNA as a probe. The

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Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis

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