Cathepsin B aggravates acute pancreatitis by activating the NLRP3 inflammasome and promoting the caspase-1-induced pyroptosis

Objectives: Cathepsin B (CTSB), NOD-like Receptor family pyrin domain-containing 3 (NLRP3), and Caspase-1 play an important role in the development of Acute Pancreatitis (AP). Besides, the relationship between the proteins remains poorly understood. In addition, whereas previous studies have found Caspase-1 activation in AP, Pyroptosis, a Caspase-1 induced cell death mode, has never been proposed and proved in AP.

Methods: We induced AP in mice by intraperitoneal injection of cerulein. Mice in the inhibitor group of CTSB were pretreated with injection of CA-074me, while mice in the inhibitor group of Caspase-1 were of Ac-YVAD-CHO, 1 h earlier. We evaluated the inflammation of the pancreas and the detected expression of activated CTSB, NLRP3, ASC, caspase-1p20, IL-1β and IL-18. TUNEL staining was used to detect acinar cell death.

Results: The inflammation of the pancreas in the two inhibitor groups was significantly reduced compared with that in the AP group. We observed that CA-074me not only inhibits CTSB, but also suppresses the expression and activity of NLRP3, ASC and Caspase-1. We found that CA-074me further inhibits the downstream event of Caspase-1, including pro-inflammatory cytokine secretion and Pyroptosis. Whereas Ac-YVAD-CHO inhibited Caspase-1 and decreased pro-inflammatory cytokine secretion and Pyroptosis, it did not down-regulate the expression and activity ofCTSB, NLRP3 and ASC.

Conclusion: The results indicate that CTSB may aggravate AP by activating the NLRP3 inflammasome and promoting Caspase-1-induced Pyroptosis. These provide clues about the pathophysiological mechanisms of AP, shedding light on new ideas and potential targets for the prevention and treatment of AP.