Neutrophils in beige mice secrete normal amounts of cathepsin G and a 46 kDa latent form of elastase that can be activated extracellularly by proteolytic activity

Among other phenotypic defects, the beige mouse is susceptible to infection and has large neutrophil granules that apparently secrete a decreased amount of elastolytic activity. We have shown using in vitro methods that cytosolic inhibitors in beige neutrophils are normal, Although cathepsin G is tightly bound to lysosomal membranes, normal amounts of activity are released in response to degranulating agents. Decreased elastolytic activity is secreted by beige neutrophils because elastase is present in the granules as a 46 kDa proenzyme, which can be activated extracellularly by a protease-dependent mechanism. The current experiments were undertaken to explore the in vivo functions of neutrophils from C57 BI/6J (bg/bg) beige mice using the model of casein-induced acute peritonitis; normal C57 BI/6J (+/+) mice served as controls. The kinetics of neutrophil accumulation in the peritoneum were normal, suggesting normal neutrophil migration. Cathepsin G activity in the cell-free supernatant of peritoneal lavage fluid was normal; elastolytic activity was initially very low but increased to about twice baseline level after 4 h at 25 degrees C and to about 20-fold at 36 h. The appearance of this activity was inhibited to varying degree (54 to 83%) by different protease inhibitors (pepstatin, antipain, aprotinin, leupeptin and chymostatin), We conclude that the decreased amount of elastolytic activity secreted by beige neutrophils into an inflammatory exudate is due to a genetic defect that results in production of a 46 kDa proelastase rather than the normal 29 kDa active elastase; the proelastase can be spontaneously activated by a protease-dependent mechanism. In light of these data, the use of the beige mouse as a model for the Chediak-Higashi syndrome, and as a model in which neutrophils do not produce elastase, must be reconsidered.