CTSC is a regulator and activator of various lysosomal enzymes such as cathepsin B, D, and L. Its loss mitigates the severity of pancreatitis not by reducing intra-acinar cell zymogen activation but by reducing infiltration of neutrophil granulocytes into the pancreas.
Intra-pancreatic trypsinogen activation by cathepsin B can occur in ferrets, which might trigger pancreatitis even in the absence of trypsinogen autoactivation.
Of note, the CTSD KO greatly reduced CTSB and trypsinogen activation in acinar cells, and CTSD directly activated CTSB but not trypsinogen <i>in vitro</i> During pancreatitis in pancreas-specific CTSD<sup>f/f</sup>/p48<sup>Cre/+</sup> animals, markers of severity were reduced only at 1 h, whereas in the complete KO, this effect also included the late disease phase (8 h), indicating an important effect of extra-acinar CTSD on course of the disease.
The accelerated activation of p.K23_I24insIDK by cathepsin B is a unique biochemical property not found in any other pancreatitis-associated trypsinogen mutant.
These observations confirm the presence of active cathepsin B in the human pancreatic secretory pathway and are consistent with the notion that cathepsin B-mediated trypsinogen activation might play a pathogenic role in human pancreatitis.
These observations confirm the presence of active cathepsin B in the human pancreatic secretory pathway and are consistent with the notion that cathepsin B-mediated trypsinogen activation might play a pathogenic role in human pancreatitis.