Neutrophil elastase activity compensates for a genetic lack of matrix metalloproteinase‐9 (MMP‐9) in leukocyte infiltration in a model of experimental peritonitis

Extracellular proteolysis of basement membranes and matrix is required for leukocyte diapedesis and migration to the inflammatory fo- cus. Neutrophil elastase (NE) and matrix metallo- proteinases (MMPs) are among the enzymes in- volved in these processes, as shown in mice genet- ically deprived of such enzymes. However, studies with MMP-9 / mice revealed that albeit neutro- phil influx is impaired initially in these animals versus controls, neutrophilia is subsequently aug- mented during later stages of zymosan peritonitis. MMP-9 as a MMP and NE as a serine protease belong to different enzyme classes. As MMP-9 and NE are produced by neutrophils and have similar biological effects on matrix remodeling, it was evaluated whether enhanced NE activity might compensate for the lack of MMP-9. In genetically uncompromised mice, two waves of NE expression and activity during zymosan peritonitis were ob- served in inflammatory neutrophils and macro- phages at the time of influx of the respective cell populations into the peritoneum. Additionally, NE expression was associated with the activity of resi- dent peritoneal mast cells and macrophages, as their depletion reduced NE activity. Most impor- tantly, the NE mRNA and protein expression and activity were enhanced significantly in MMP-9 / mice during late stages of zymosan peritonitis. In addition, the application of a selective NE inhibitor restrained enhanced neutrophil accumulation sig- nificantly. In conclusion, during acute peritoneal inflammation, NE expression and activity increase gradually, facilitating leukocyte influx. Moreover, increased NE activity might compensate for a ge- netic lack of MMP-9 (as detected in MMP-9 / mice), resulting in delayed accumulation of neutro- phils during late zymosan peritonitis. J. Leukoc. Biol. 85: 374-381; 2009.