2. Academic Validation
  3. Diabetes induces hepatocyte pyroptosis by promoting oxidative stress-mediated NLRP3 inflammasome activation during liver ischaemia and reperfusion injury

Diabetes induces hepatocyte pyroptosis by promoting oxidative stress-mediated NLRP3 inflammasome activation during liver ischaemia and reperfusion injury

  • Ann Transl Med. 2020 Jun;8(12):739. doi: 10.21037/atm-20-1839.
Chengyu Shi 1 2 3,  Qi Wang 1 2 3 4,  Zhuqing Rao 5,  Yong Shi 1 2 3,  Song Wei 1 2 3 4,  Hao Wang 1 2 3,  Xu Lu 1 2 3,  Ping Wang 1 2 3,  Ling Lu 1 2 3 4 6,  Haoming Zhou 1 2 3,  Feng Cheng 1 2 3
Affiliations

Affiliations

  • 1 Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Research Unit of Liver Transplantation and Transplant Immunology, Chinese Academy of Medical Sciences, Nanjing, China.
  • 2 Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China.
  • 3 NHC Key Laboratory of Living Donor Liver Transplantation, Nanjing, China.
  • 4 School of Medical, Southeast University, Nanjing, China.
  • 5 Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 6 Department of General Surgery, People's Hospital of Qinghai Province, Xining, Qinghai, China.
PMID: 32647664 DOI: 10.21037/atm-20-1839
Abstract

Background: Although diabetes mellitus has been reported to aggravate liver ischaemia and reperfusion (IR) injury, the basic mechanism remains largely unknown. The object of the present study was to determine the role of oxidative stress and hepatocellular Pyroptosis in liver IR injury in diabetic mice.

Methods: Db/db and C57BL/6 mice at 8 weeks of age were subjected to liver IR injury. Liver injury and hepatocyte cell death were analyzed. A NOD-like receptor family pyrin domain-containing 3 protein (NLRP3) inflammasome antagonist (CY09) and a Reactive Oxygen Species (ROS) antagonist (N-Acetyl-L-cysteine, NAC) were used to determine the role of ROS-mediated hepatocellular Pyroptosis in diabetic mice post-IR.

Results: Aggravated liver IR injury was found in db/db mice compared to C57BL/6 control mice, as demonstrated by increased serum alanine aminotransaminase (ALT) and aspartate aminotransaminase (AST) levels, liver architecture damage and Suzuki scores. Interestingly, IR induces the Pyroptosis of hepatocytes in db/db mice, as evidenced by enhanced NLRP3 inflammasome activation, increased numbers of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive hepatocytes and increased gene expression of interleukin-1β (IL-1β) and IL-18 in livers post-IR. The inhibitory effect of CY09, an NLRP3 antagonist, efficiently abrogated the exacerbation effects of diabetes on liver IR injury in db/db mice. Furthermore, increased ROS expression was detected in db/db mice compared to control mice after IR. ROS scavenging by NAC pretreatment markedly inhibited hepatocellular NLRP3 inflammasome activation and Pyroptosis in the db/db mice post-IR, indicating that ROS play an essential role in mediating hepatocyte Pyroptosis in the setting of diabetes mellitus.

Conclusions: Our results demonstrate that diabetes induces hepatocyte Pyroptosis by promoting oxidative stress-mediated NLRP3 inflammasome activation during liver IR injury. Strategies targeting ROS and NLRP3 inflammasome activation would be beneficial for preventing liver IR injury in diabetic patients.

Keywords

Diabetes; NOD-like receptor family pyrin domain-containing 3 protein inflammasome (NLRP3 inflammasome); hepatic ischaemia and reperfusion injury (hepatic IR injury); pyroptosis; reactive oxygen species (ROS).

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