Necroptotic Cell Death in Liver Transplantation and Underlying Diseases: Mechanisms and Clinical Perspective

Abstract

Cell death is a natural process for the turnover of aged cells, but it can also arise as a result of pathological conditions. Cell death is recognized as a key feature in both acute and chronic hepatobiliary diseases caused by drug, alcohol, and fat uptake; by viral infection; or after surgical intervention. In the case of chronic disease, cell death can lead to (chronic) secondary inflammation, cirrhosis, and the progression to liver cancer. In liver transplantation, graft preservation and ischemia/reperfusion injury are associated with acute cell death. In both cases, so‐called programmed cell death modalities are involved. Several distinct types of programmed cell death have been described of which apoptosis and necroptosis are the most well known. Parenchymal liver cells, including hepatocytes and cholangiocytes, are susceptible to both apoptosis and necroptosis, which are triggered by distinct signal transduction pathways. Apoptosis is dependent on a proteolytic cascade of caspase enzymes, whereas necroptosis induction is caspase‐independent. Moreover, different from the “silent” apoptotic cell death, necroptosis can cause a secondary inflammatory cascade, so‐called necroinflammation, triggered by the release of various damage‐associated molecular patterns (DAMPs). These DAMPs activate the innate immune system, leading to both local and systemic inflammatory responses, which can even cause remote organ failure. Therapeutic targeting of necroptosis by pharmacological inhibitors, such as necrostatin‐1, shows variable effects in different disease models.

Necroptosis in Cholangiocarcinoma

“…For instance, intracellular factors such as TNFα, the Fas ligand, the tumor necrosis factor-related apoptosis-inducing ligand, interferon γ, double-stranded RNA, and adenosine triphosphate (ATP) depletion, are known to induce necroptosis, as well as extracellular events, such as the production of ROS, calcium overload, and ischemia/reperfusion injury (IRI) [5,17,18]. All these stimuli act by binding death receptors, including Fas, TNFα receptor 1 (TNFR1), and pathogen-induced receptors, such as certain toll-like receptors (TLRs) and Z-DNA binding protein 1 [5,18,19]. Whereas the downstream cascades activated by TNFR1 have been relatively well-studied, the description of other pathways is limited to a few models and publications.…”

“…TNFα/TNFR1 binding promotes not only necroptosis, but also caspase-dependent apoptosis and activation of the nuclear factor-kappa B (NF-κB) pathway, which trigger the formation of pro-inflammatory and pro-survival complexes ( Figure 1) [18,19].…”

“…Picture adopted from Vandenabeele et al [20]. TNFR1 activation leads to the formation of the so-called complex I by recruiting TNFR1associated death domain (TRADD), TNFR-associated factor 2, RIPK1, the cellular inhibitor of apoptosis protein (cIAP) 1-2, and the linear ubiquitin chain assembly complex [18]. Upon the formation of complex I, different signaling complexes can follow, which can determine CD or Figure 1.…”

“…Notably, the deubiquitylation of RIPK1 can also be directly promoted by drugs, such as the so-called second mitochondrial activator of caspases (Smac) mimetics [23]. The association of Fas-associated protein with the death domain (FADD), TRADD, FLICE-inhibitory protein (FLIP), and pro-caspase-8 forms cytosolic complex IIa, and the activation of pro-caspase-8 into caspase-8, promotes RIPK1-independent apoptosis [4,18]. However, in the case of knockdown of the NF-κB essential modulator or blockage of cIAPs or transforming growth factor β-activated kinase 1 (TAK1), FADD, FLIP, and pro-caspase-8 bind RIPK1 and RIPK3, forming complex IIb, which is involved in RIPK1-dependent apoptosis [18,19].…”

“…The association of Fas-associated protein with the death domain (FADD), TRADD, FLICE-inhibitory protein (FLIP), and pro-caspase-8 forms cytosolic complex IIa, and the activation of pro-caspase-8 into caspase-8, promotes RIPK1-independent apoptosis [4,18]. However, in the case of knockdown of the NF-κB essential modulator or blockage of cIAPs or transforming growth factor β-activated kinase 1 (TAK1), FADD, FLIP, and pro-caspase-8 bind RIPK1 and RIPK3, forming complex IIb, which is involved in RIPK1-dependent apoptosis [18,19]. On the contrary, when caspase-8 is down-regulated or inhibited, RIPK1 interacts with RIPK3 and MLKL to form complex IIc, also called the necrosome, by which necroptosis is initiated [4,18].…”