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Review
, 25 (7), 1091-1104

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

Affiliations
Review

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

Shaojun Shi et al. Liver Transpl.

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.

Figures

Figure 1
Figure 1
Distinct molecular and morphologic features of apoptotic, necroptotic, and necrotic cell death. (A) Molecular pathways of cell death in PLCs. The binding of TNF‐α and TNFR1 recruits TRADD, TRAF2, RIPK1, cIAP1/2, and LUBAC and forms the complex I leading to the activation of the NF‐κB signaling and a prosurvival pathway. Following the dissociation from TNFR1, complex I is transformed into complex IIa, which includes TRADD, FADD, FLIPs, and procaspase 8, and contributes to the activation of caspase 8 and subsequent RIPK1‐independent apoptosis. Hyperactivation of cylindromatosis (CYLD) deubiquitinates RIPK1 and thus destabilizes complex I and promotes the formation of complex IIb, which is involved in RIPK1‐dependent apoptosis. Complex IIb consists of RIPK1, RIPK3, FADD, FLIPs, and caspase 8, and it can be promoted by inhibition of NEMO, cIAPs, or TAK1. Nevertheless, once caspase 8 is inhibited, RIPK3 is activated to interact with RIPK1 and binds to MLKL, forming the complex IIc (necrosome) by which necroptosis is promoted. RIPK3 phosphorylates MLKL in the complex IIc and thereby triggers oligomerization of MLKL, driving the permeabilization step. Nonprogrammed cell death by necrosis is characterized by mitochondrial impairment with resulting ATP depletion and triggering of the ROS‐JNK loop. After the cell membrane ruptures in necrotic or necroptotic cells, intracellular DAMPs are released and act as activators and amplifiers of necroinflammation. Conversely, release of a lower amount of DAMPs from apoptotic cells leads to much milder necroinflammation. (B) Summary of hallmark events and characteristics of cell survival and cell death by apoptosis, necroptosis, or necrosis.
Figure 2
Figure 2
Schematic overview of necrosis and necroinflammation during liver transplantation. During ischemia and reperfusion injury, both necroptosis and necrosis of PLCs can occur. Rupture of the cell membrane facilitates the release of intracellular DAMPs and subsequent inflammatory responses. TLRs on both KCs and DCs are activated that promote the production and release of cytokines and chemokines. This will trigger migration of innate immune cells to the liver graft but also give rise to necrotic spread by further induction of necroptosis in surrounding cells. This necrotic spread could cause early allograft dysfunction or total graft failure causing primary nonfunction. Furthermore, this necrotic spread and necroinflammation can lead to remote organ injury outside the graft. Robust innate immunity can also active host T cells and evoke adaptive immune response that is associated with acute and chronic rejection after transplantation.

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