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

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

  • Int Immunopharmacol. 2021 May;94:107496. doi: 10.1016/j.intimp.2021.107496.
Jianhua Wang 1 Lichun Wang 1 Xiaofei Zhang 1 Yanfen Xu 2 Lei Chen 3 Weiyu Zhang 4 Enhe Liu 1 Chaoxing Xiao 1 Qiuye Kou 5
Affiliations

Affiliations

  • 1 Department of Intensive Care Unit, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510655, China.
  • 2 Department of Gastroenterology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China.
  • 3 Department of Intensive Care Unit, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510655, China. Electronic address: chenlei6@mail.sysu.edu.cn.
  • 4 Department of Neurosurgery, the Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai 519000, China.
  • 5 Department of Intensive Care Unit, the Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510655, China. Electronic address: kouqiuye@126.com.
Abstract

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.

Keywords

Acute pancreatitis; Caspase-1; Cathepsin B; Gasdermin D; NLRP3 inflammasome; Pyroptosis.

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