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

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. • 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.