Page 225 - Clinical Immunology_ Principles and Practice ( PDFDrive )

204 ParT ONE Principles of Immune Response

and electron microscopy, suggests a central role of swelling of KEY CONCEPTS
this organelle and MOMP, as in apoptosis. Overlapping data
point to the triggers of the loss of mitochondrial membrane Prototype Inhibitors of Regulated Necrosis
integrity, most prominently the pathways of mitochondrial • Inhibitors of necroptosis
permeability transition (MPT)–induced regulated necrosis • Necrostatin-1 (Nec-1)
(MPT-RN) and parthanatos (see below). • Nec-1s (Nec-1 stable)
Recently, the idea that “mitochondrial necrosis” is just an • Ponatinib
upstream event to “metabolic cell death,” which certainly would • Inhibitors of ferroptosis
involve ferroptosis and probably could be a trigger for necroptosis • Ferrostatin-1 (Fer-1)
• 16-86
as well, started to emerge, but this requires further evaluation. • Liproxstatin-1
Ferroptosis may be considered “mitochondrial” cell death, but • Inhibitors of mitochondrial permeability transition (MPT)–induced
−
the key regulators GPX4 and system Xc are clearly outside of regulated necrosis (MPT-RN)
mitochondria, so we do not classify ferroptosis in this section • Cyclosporine (CsA)
despite the role of mitochondria in this particular cell death • Sanglifehrin A (SfA)
subroutine. For this chapter, we separate MPT-RN from par- • Inhibitors of parthanatos
• Olaparib and many others
thanatos. Although there are doubts about the correct classifica- • Inhibitors of pyroptosis
tion of mitochondrial cell death, evidence from genetically • zVAD-fmk (nonspecific caspase inhibitor)
modified animals leaves no doubt about the in vivo • Others to be developed
relevance.
MPT-RN
MPT-RN is the consequence of mitochondrial permeability CONCLUDING REMARKS AND IMPLICATIONS FOR
transition, a highly effective shortcut between the mitochondrial SOLID-ORGAN TRANSPLANTATIONS
matrix and the cytosol. MPT is mediated through a pore (the
MPT pore [MPTP]), the composition of which has been a matter Understanding the pathways of RN will allow screening for and/
of debate for at least 2 decades. A current widely accepted model or design of specific inhibitors of the enzymes involved. Two
assumes a multiprotein complex physically or functionally major effects are expected from inhibiting RN. First, in clinically
involving proteins from the mitochondrial matrix, inner and relevant conditions in which necrosis is the main determinant,
outer mitochondrial membranes, the transmembrane space, and such as stroke, myocardial infarction, sepsis, transplantation,
the cytosol. The pore is controlled by a cyclophilin named acute liver failure, pancreatitis, and the center of solid tumors,
cyclophilin D (CYPD), a key modulator of MPTP opening and it remains to be investigated how beneficial an antinecrosis therapy
thus MPT-RN. Genetic absence of CYPD protects mice from might be. Second, and probably of at least equal importance,
diverse in vivo challenges, including stroke, myocardial infarction, necroinflammation deteriorates and amplifies the primary organ
and renal ischemia–reperfusion injury. As with other cyclophilins, damage.
the immunosuppressant cyclosporine (CsA) inhibits the opening In transplantation, standard immunosuppression is tailored
of the MPTP and therefore prevents MPT-RN. This effect may to preventing proliferation of immune cells, but it does not
well account for some of the immunosuppressive function of prevent the priming of memory B cells. To transplant an organ
CsA. Other models, however, favor CYPD to interact with the full of DAMPs after a long period of organ transfer may be the
2+
21
c subunit of F 1 F 0 –ATPase complex. Ca is a well-known trigger strongest possible stimulus for memory B cells, which can only
2+
of MPT-RN in vitro, but it remains largely unclear how Ca expand upon tapering of the immunosuppression. That is exactly
triggers persistent MPT, which probably results in AIF release the time when antibody-mediated rejection (ABMR) becomes
22
from mitochondria to the cytosol. a major factor, lasting over years. Importantly, this does not
happen to a comparable extent in living donor transplantations
Parthanatos despite full HLA mismatch and blood group incompatibilities.
Parthanatos is defined as cell death that occurs following so-called The upcoming years of RN and transplantation research should
overactivation of the DNA repair enzyme poly [ADP-ribose] clarify how an anti-RN therapy may improve the outcome of
polymerase 1 (PARP1). PAR polymers are formed and translocate transplants with a particular focus on ABMR (Table 13.1).
to the outer mitochondrial membrane by unknown targeting
mechanisms. The default induction of PARP1 overactivation
include a wide array of stimuli, ranging from DNA damage ON THE HOrIZON
(e.g., through irradiation) overreactive oxygen species stress to In Vivo Interference With Regulated Necrosis
induction by toxins, such as methylnitronitrosoguanidine
(MNNG). Comparable to MPT-RN, parthanatos results in AIF • Receptor-interacting protein kinase 1 (RIPK1) inhibitors show promising
release. It has been suggested that AIF requires active PARP1 to results in animal studies/human phase I studies. Currently, they are
the first-in-class compounds to prevent necrosis.
+
transfer ATP-ribose groups from NAD onto its targets. Interest- • Ferroptosis inhibitors have the potential to stop the necroinflammatory
ingly, most of our knowledge of PARP1 originates from circle. First trials in humans are urgently awaited.
cancer research. Many tumors have been demonstrated to • As immune-checkpoint therapy becomes more and more the therapeutic
overactivate PARP1, and PARP inhibitors are in the FDA approval standard for several cancers, questions will arise if induction of regulated
process for diverse cancers as a result of promising outcomes of necrosis (RN; to produce damage-associated molecular patterns
phase III clinical trials. For BRCA1/2 mutated ovarian and breast [DAMPs]) and checkpoint blockade (to release autoimmune breaks)
could work in a similar fashion.
cancer, PARP-inhibitor olaparib has already been introduced in • Most importantly, it is possible to interfere with necrosis!
clinical practice.