NADPH Oxidase Restrains the Matrix Metalloproteinase Activity of Macrophages

Xiaoyun Fu,William C Parks,Sean Y Kassim,W Conrad Liles,Jay W Heinecke,Steven D Shapiro

doi:10.1074/jbc.m503292200

Xiaoyun Fu, William C Parks + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m503292200

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Abstract

Matrix metalloproteinases (MMPs) regulate numerous functions in normal and disease processes; thus, irreversibly blocking their activity is a key step in regulating MMP catalysis. We previously showed in vitro that oxidizing intermediates generated by phagocytes inactivate MMPs by modifying specific amino acids. To assess whether this mechanism operates in vivo, we focused on MMP-12, a macrophage-specific MMP known to mediate emphysema in mouse models. We found that mice lacking gp91(phox), a phagocyte-specific component of the NADPH oxidase, developed extensive, spontaneous emphysematous destruction of their peripheral air spaces, whereas mice deficient in both NADPH oxidase and MMP-12 were protected from spontaneous emphysema. Although gp91(phox)-null and wild-type macrophages produced equivalent levels of MMP-12 protein, the oxidant-deficient cells had greater MMP-12 activity than wild-type macrophages. These findings indicate that reactive intermediates provide a physiological mechanism to protect tissues from excessive macrophage-mediated damage during inflammation.

Highlights

Matrix metalloproteinases (MMPs) regulate numerous functions in normal and disease processes; irreversibly blocking their activity is a key step in regulating MMP catalysis
To assess whether this mechanism operates in vivo, we focused on MMP-12, a macrophage-specific MMP known to mediate emphysema in mouse models
We found that mice lacking gp91phox, a phagocyte-specific component of the NADPH oxidase, developed extensive, spontaneous emphysematous destruction of their peripheral air spaces, whereas mice deficient in both NADPH oxidase and MMP-12 were protected from spontaneous emphysema

Summary

NADPH Oxidase Restrains the Matrix Metalloproteinase Activity of Macrophages*

We previously showed in vitro that oxidizing intermediates generated by phagocytes inactivate MMPs by modifying specific amino acids To assess whether this mechanism operates in vivo, we focused on MMP-12, a macrophage-specific MMP known to mediate emphysema in mouse models. Gp91phox-null and wild-type macrophages produced equivalent levels of MMP-12 protein, the oxidant-deficient cells had greater MMP-12 activity than wild-type macrophages These findings indicate that reactive intermediates provide a physiological mechanism to protect tissues from excessive macrophage-mediated damage during inflammation. We demonstrated that oxidants potently and efficiently inactivate matrilysin (MMP-7) by cross-linking adjacent tryptophan-glycine residues within the catalytic domain of the enzyme [14, 15] These in vitro observations suggest that MMP inactivation can occur on or near phagocytes that produce both MMPs and reactive intermediates. Our findings indicate that oxidants may function to govern, rather than promote, inflammatory processes

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