TNFα-Mediated Necroptosis Aggravates Ischemia-Reperfusion Injury in the Fatty Liver by Regulating the Inflammatory Response

Abstract

Nonalcoholic fatty liver disease (NAFLD) is more sensitive to ischemia and reperfusion injury (IRI), while there are no effective methods to alleviate IRI. Necroptosis, also known as “programmed necrosis,” incorporates features of necrosis and apoptosis. However, the role of necroptosis in IRI of the fatty liver remains largely unexplored. In the present study, we aimed to assess whether necroptosis was activated in the fatty liver and whether such activation accelerated IRI in the fatty liver. In this study, we found that the liver IRI was enhanced in HFD-fed mice with more release of TNFα. TNFα and supernatant of macrophages could induce necroptosis of hepatocytes in vitro. Necroptosis was activated in NAFLD, leading to more severe IRI, and such necroptosis could be inhibited by TN3-19.12, the neutralizing monoclonal antibody against TNFα. Pretreatment with Nec-1 and GSK′872, two inhibitors of necroptosis, significantly reduced the liver IRI and ROS production in HFD-fed mice. Moreover, the inhibition of necroptosis could decrease ROS production of hepatocytes in vitro. Inflammatory response was activated during IRI, and necroptosis inhibitors could suppress signaling pathways of inflammation and the soakage of inflammation cells. In conclusion, TNFα-induced necroptosis played an important role during IRI in the fatty liver. Our findings demonstrated that necroptosis might be a potential target to reduce the fatty liver-associated IRI.

Hepatic CEACAM1 expression indicates donor liver quality and prevents early transplantation injury

“…The latter mount a cascade of innate immune-dominated inflammatory responses during the reperfusion phase, accelerating the hepatocellular OLT damage and undermining long-term survival and clinical outcomes. Although cell death during the reperfusion phase appears to proceed primarily via oncotic necrosis (3,4), consistent with our own and others' studies demonstrating the contribution of apoptosis and necroptosis in IRI pathology (5)(6)(7), the hepatocellular death program at the reperfusion phase may encompass a mixture of diverse molecular mechanisms. Although the restoration of hepatic blood flow is the principal cause of tissue injury, pretransplant cold storage itself can trigger organ damage as well (8).…”

Maresin 1, a Proresolving Lipid Mediator, Ameliorates Liver Ischemia-Reperfusion Injury and Stimulates Hepatocyte Proliferation in Sprague-Dawley Rats

“…There are several strategies under development related to improve the IR damage, including improvements in donor organ perfusion and preservation methods, pharmacologic treatments, gene therapy, and surgical techniques, among others. There is evidence that IR not only generates complications, but also ameliorates survival in an animal model [11]. For the aforementioned reasons, IR surgery is a still a challenge in the clinical setting.…”

“…Necroptosis is a novel mode of cell death, known as "programed necrosis", which is controlled by two kinase receptor-interacting proteins (RIP1 and RIP3) [11]. RIP3 and the necrosome have shown controversial results in IR.…”

Necroptosis in Cholangiocarcinoma

“…Different groups have demonstrated the involvement of necroptosis in IRI during orthotopic liver transplantation, both in murine cell lines and mouse IRI models [18]. In this setting, an increased expression of necroptosis mediators has been described, and different inhibitors have been used to block the necroptotic cascade [3,18,55,[86][87][88][89][90][91][92].…”