NADPH oxidase restrains the matrix metalloproteinase activity of macrophages.
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.
Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
Sean Y
SY
Kassim
Xiaoyun
X
Fu
W Conrad
WC
Liles
Steven D
SD
Shapiro
William C
WC
Parks
Jay W
JW
Heinecke
D000818:Animals; D002384:Catalysis; D003433:Crosses, Genetic; D016207:Cytokines / Q000378:metabolism; D004646:Emphysema / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism / Q000494:pharmacology; D007249:Inflammation; D008264:Macrophages / Q000201:enzymology* / Q000378:metabolism; D053508:Matrix Metalloproteinase 12; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010100:Oxygen / Q000378:metabolism; D010586:Phagocytes / Q000378:metabolism; D010587:Phagocytosis; D013997:Time Factors
D016207:Cytokines; D008562:Membrane Glycoproteins; D006861:Hydrogen Peroxide; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D020782:Matrix Metalloproteinases; D008666:Metalloendopeptidases; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12; D010100:Oxygen