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Mouse model suggests limited role for human mesotrypsin in pancreatitis
Dóra Mosztbacher1, Miklós Sahin-Tóth2
1Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University, Henry M. Goldman School of Dental Medicine, Boston, MA, 02118, United States.
Abstract:
Mesotrypsin is a low-abundance human trypsin isoform with a unique evolutionary mutation that conferred resistance to trypsin inhibitors and restricted substrate specificity. Mesotrypsin degrades the serine protease inhibitor Kazal type 1 (SPINK1) and thereby might increase risk for pancreatitis. Here, we report a mouse model designed to test the role of mesotrypsin in pancreatitis. We introduced the human mesotrypsin evolutionary signature mutation into mouse cationic trypsinogen (isoform T7), resulting in a Gly to Arg change at the corresponding position 199. In biochemical experiments using purified proteins, the p.G199R T7 mutant recapitulated all salient features of human mesotrypsin. T7G199R mice developed normally with no spontaneous pancreatitis or other obvious phenotypic changes. Cerulein-induced acute pancreatitis in C57BL/6N and T7G199R mice showed similar severity with respect to inflammatory parameters and acinar cell necrosis while plasma amylase activity was higher in T7G199R mice. Neither SPINK1 degradation nor elevated intrapancreatic trypsin activation was apparent in T7G199R mice. The results indicate that in T7G199R mice the newly created mesotrypsin-like activity has no significant impact on cerulein-induced pancreatitis. The observations suggest that human mesotrypsin is unimportant for pancreatitis; a notion that is consistent with published human genetic studies.
Insights
This study created a mouse model for human mesotrypsin, a trypsin variant linked to pancreatitis risk. The model showed mesotrypsin did not significantly impact pancreatitis development, suggesting it may not be a major factor in the disease.
Area of Science:
- Biochemistry
- Genetics
- Gastroenterology
Background:
- Mesotrypsin is a human trypsin isoform with mutations conferring inhibitor resistance and altered substrate specificity.
- Mesotrypsin degrades SPINK1, potentially increasing pancreatitis risk.
Purpose of the Study:
- To develop and validate a mouse model for human mesotrypsin.
- To investigate the role of mesotrypsin in pancreatitis using this model.
Main Methods:
- Introduced the human mesotrypsin mutation (G199R) into mouse cationic trypsinogen (T7).
- Biochemical characterization of the purified mutant protein.
- Induction of acute pancreatitis using cerulein in wild-type and T7G199R mice.
- Assessment of inflammatory parameters, acinar cell necrosis, plasma amylase, SPINK1 degradation, and trypsin activation.
Main Results:
- The T7G199R mutant protein exhibited human mesotrypsin characteristics.
- T7G199R mice showed no spontaneous pancreatitis or developmental abnormalities.
- Cerulein-induced pancreatitis severity was similar in both mouse groups, with higher amylase in T7G199R mice.
- No significant SPINK1 degradation or increased trypsin activation was observed in T7G199R mice during pancreatitis.
Conclusions:
- The mesotrypsin-like activity in T7G199R mice did not significantly affect cerulein-induced pancreatitis.
- These findings suggest human mesotrypsin may not be a significant factor in pancreatitis development.
- Results align with human genetic studies indicating a limited role for mesotrypsin in pancreatitis.
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