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Review
. 2019 Feb;24(1):12-19.
doi: 10.1097/MOT.0000000000000599.

Tumor Necrosis Factor-Driven Cell Death in Donor Organ as a Barrier to Immunological Tolerance

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Free PMC article
Review

Tumor Necrosis Factor-Driven Cell Death in Donor Organ as a Barrier to Immunological Tolerance

Rosalind L Ang et al. Curr Opin Organ Transplant. .
Free PMC article

Abstract

Purpose of review: Regulated cell death (RCD) is likely to play a role in organ rejection but it is unclear how it may be invoked. A well-known trigger of regulated cell death is tumor necrosis factor-alpha (TNF), which activates both caspase-dependent apoptosis and caspase-independent necroptosis. TNF is best known as a pro-inflammatory cytokine because it activates NFκB and MAPK signaling to induce expression of pro-inflammatory genes.

Recent findings: Emerging data from animal models now suggest that TNF-induced cell death can also be inflammatory. Therefore, the role of cellular demise in regulating immunity should be considered. In transplantation, TNF could have a role in cellular injury or death from ischemia reperfusion (IR) injury and this may dictate organ survival. The default response to TNF in most cells is survival, rather than death, because of the presence of cell death checkpoints. However, cells succumb to TNF-driven death when these checkpoints are disrupted, and sensitivity to death likely reflects a reduction in molecules that fortify these checkpoints. We propose that a cell's propensity to die in response to TNF may underlie allograft rejection.

Summary: Genetic, epigenetic, and posttranslational control of death checkpoint regulators in donor tissues may determine graft survival. Therapeutically, drugs that prevent donor cell demise could be useful in preventing organ rejection.

Conflict of interest statement

Conflicts of interest

We declare that there are no financial conflicts of interest.

Figures

Figure 1
Figure 1. Schematic of the cell death checkpoints in the TNFR1 signaling pathway.
(A) In most cells, there are two sequential cell death checkpoints in the TNFR1 signaling pathway and ligand binding to TNFR1 does not trigger cell death. The early checkpoint occurs when RIPK1 is modified by K63- and M1-linked poly-ubiquitin chains catalyzed by the TRAF2/cIAP1/2 and LUBAC E3 ligases, respectively. RIPK1 is in a pro-survival mode and is prevented from associating with the FADD/CASPASE 8 death-signaling complex. This checkpoint is reinforced by IKK-mediated phosphorylation of RIPK1 and CYLD to further inhibit their death-signaling capabilities. The late checkpoint occurs when NFκB translocates to the nucleus to upregulate expression of pro-survival genes. If these checkpoints function properly, cells do not die in response to TNF. (B) Failure in the early checkpoint occurs when ubiquitination of RIPK1 is impaired. This can happen when expression or activity of the ubiquitin E3 ligases (e.g., TRAF2, cIAP1/2, LUBAC) is blocked, or when the expression or activity of deubiquitinases (e.g., CYLD) is elevated. A reduction in ubiquitin chains on RIPK1 promotes its interaction with FADD and CASPASE 8 to induce apoptosis, or with RIPK3 to induce necroptosis if apoptosis is inhibited. The RIPK1-dependent death can then lead to inflammation.
Figure 2
Figure 2. TNF death sensitivity contributes to allograft rejection in multiple ways.
(A) Following extended cold storage and subsequent surgical implantation, the donor organ undergoes ischemia reperfusion, which could cause cell death and injury. We propose that TNF-mediated death contributes to the IR injury and the degree of cell death is determined by the expression level of early checkpoint regulators intrinsic to the donor organ. For example, if cells within the organ from a particular donor express high level of LUBAC but low level of CYLD, those cells would be more resistant to TNF-induced cell death. That organ may be less prone to injury and rejection. Conversely, a donated organ with low LUBAC but high level of CYLD expression would be more sensitive to cell death and more likely to be rejected. (B) In a susceptible donor organ, debris from cells dying from either RIPK1-dependent apoptosis or necroptosis contain allo-antigens and damage-associated molecular patterns (DAMPs). Pattern-recognition receptors on dendritic cells sense these DAMPs resulting in their activation and enhanced presentation of allo-antigens to T cells. The activated allo-reactive T cells then kill donor cells by producing IFNγ and releasing cytotoxic granules containing perforin. The initial TNF-induced cell death occurring during IR eventually lead to the induction of T cell effectors that now destroy donor cells. (C) In addition to perforin-mediated lysis, activated allo-reactive CD8 T cells can also express TNF. In a death-susceptible organ due to lowered expression of pro-survival regulators of the early checkpoint, donor cells can also be killed by the TNF released from the CD8 T cells. Furthermore, other immune cells (e.g., macrophages, monocytes and NK cells) that are also recruited to the donor organ can also produce TNF. These other TNF-producing cells are now cytotoxic if the donor cells have a defective checkpoint and now interpret TNF to be a death signal. The overall balance between pro-survival and pro-death molecules of the TNF pathway determines cell fate and graft survival. Therapeutic agents that reinforce the early checkpoint and block death-signaling proteins could be useful in enhancing allograft survival.

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