Matrix metalloproteinase 9 (MMP-9) is a Zn(2+)-dependent
endopeptidase that degrades some of the components of basement membranes and extracellular matrix and thus participates in leukocyte infiltration during
inflammation. In a model of
zymosan peritonitis, neutrophil infiltration in
MMP-deficient (
MMP-9(-/-)) mice was significantly weaker at the time of their maximal influx in wild-type mice (6h). However, during the late stages of
peritonitis (24h) an extended accumulation of neutrophils was observed in
MMP-9(-/-)versus the wild-type mice. Recently, we reported that the ratio of apoptosis of inflammatory leukocytes is impaired in
MMP-9(-/-) mice during late
peritonitis and the process depends on COX-1-driven
PGE(2). Here we scrutinized the alterations in apoptotic mechanisms by comparisons between
MMP-9(-/-) and the wild-type mice. Altered apoptosis occurred only during late (24h)
peritonitis and concerned only neutrophils, and not macrophages, mast cells or lymphocytes. Furthermore, expression and activity of
caspases was altered in
MMP-9(-/-) animals, delayed for
caspase-8 and -9, and decreased in the case of
caspase-3. Also the expression of Bax/Bcl-2
proteins was changed in
MMP-9(-/-) mice. These changes, and in particular the impaired neutrophil apoptosis and weaker
caspase-3 activity, were restored by the selective COX-1 inhibition. We conclude that in mice lacking MMP-9 the enhanced COX-1-PGE(2) decreases
caspase-3 expression and activity leading to impaired apoptosis of inflammatory neutrophils resulting in abnormal accumulation of the cells at the inflammatory focus. The data also reinforce the notion that MMP-9 is a key
enzyme in neutrophil biology.