Matrix metalloproteinase-14 triggers an anti-inflammatory proteolytic cascade in endotoxemia

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2017-05, Vol.95 (5), p.487-497
• Main Authors: Aguirre, Alina, Blázquez-Prieto, Jorge, Amado-Rodriguez, Laura, López-Alonso, Inés, Batalla-Solís, Estefanía, González-López, Adrián, Sánchez-Pérez, Moisés, Mayoral-Garcia, Carlos, Gutiérrez-Fernández, Ana, Albaiceta, Guillermo M
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Animals; Biomedical and Life Sciences; Biomedicine; Endotoxemia - chemically induced; Endotoxemia - enzymology; Endotoxemia - metabolism; Female; Genotype; Human Genetics; Humans; Internal Medicine; Lipopolysaccharides - toxicity; Lung - drug effects; Lung - enzymology; Lung - metabolism; Male; Matrix Metalloproteinase 13 - genetics; Matrix Metalloproteinase 13 - metabolism; Matrix Metalloproteinase 14 - genetics; Matrix Metalloproteinase 14 - metabolism; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 8 - genetics; Matrix Metalloproteinase 8 - metabolism; Mice; Mice, Mutant Strains; Middle Aged; Molecular Medicine; Original Article; Sepsis - enzymology; Sepsis - metabolism
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-017-1510-z

ᅟ Matrix metalloproteinases can modulate the inflammatory response through processing of cyto- and chemokines. Among them, MMP-14 is a non-dispensable collagenase responsible for the activation of other enzymes, triggering a proteolytic cascade. To identify the role of MMP-14 during the pro-inflammatory response, wildtype and Mmp14 −/− mice were challenged with lipopolysaccharide. MMP-14 levels decreased after endotoxemia. Mutant animals showed 100% mortality, compared to 50% in wildtype mice. The increased mortality was related to a more severe lung injury, an impaired lung MMP-2 activation, and increased levels of the alarmin S100A9. There were no differences in the expression of other mediators including Il6 , Cxcl2 , Tgfb , Il10 , or S100a8. A similar result was observed in lung explants of both genotypes cultured in presence of lipopolysaccharide. In this ex vivo model, exogenous activated MMP-2 ameliorated the observed increase in alarmins. Samples from septic patients showed a decrease in serum MMP-14 and activated MMP-2 compared to non-septic critically ill patients. These results demonstrate that the MMP-14-MMP-2 axis is downregulated during sepsis, leading to a proinflammatory response involving S100A9 and a more severe lung injury. This anti-inflammatory role of MMP-14 could have a therapeutic value in sepsis. Key messages • MMP-14 levels decrease in lungs from endotoxemic mice and serum from septic patients. • Mmp14 −/− mice show increased lung injury and mortality following endotoxemia. • Absence of Mmp14 decreases activated MMP-2 and increases S100A9 levels in lung tissue. • MMP-14 ameliorates inflammation by promoting S100A9 cleavage by activated MMP-2.