Necrosis and apoptosis are the two major mechanisms of cell death. Necrosis is an unprogrammed form of cell death usually carried out by cells following acute injury (Ghobrial, Witzig and Adjei 2005). Necrosis can be detrimental to body tissue as it induces an inflammatory response (Fulda et al. 2010). Apoptosis is another form of cell death carried out by cells. It is a form of genetically programmed cell death with distinct biochemical steps (Fulda et al. 2010). Apoptosis, unlike necrosis, requires energy in the form of ATP. Functional mitochondria are of major importance in apoptosis. The death receptor signalling pathway is one of two major pathways involved in apoptosis. It is also commonly known as the extrinsic pathway. There are three main types of death receptors which all belong to the same super family tumor necrosis factor/nerve growth factor (TNF/NGF) (Fas et al. 2006). TNFR, FasR and TRAIL are the death receptors involved in this signalling pathway. Death receptors trigger apoptosis upon binding to a ligand. These ligands are expressed on the surface of specialised cells, for example: Fas ligand (FasL/CD95L) on activated T cells or as soluble molecules released from macrophages, B cells and T cells, for example: FasL, TRAIL, TNFα.
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Apoptotic signalling by Death Receptors
Binding of a death ligand to a death receptor oligomerises the death receptor into a trimer. This leads to the promotion of receptor clustering on cell surface. Structural changes in the death receptor intracellular domains expose regions known as death domains (DD). The exposed DD then recruit Fas- or TNF receptor-associated death domain (FADD or TRADD), these are specialised adaptor proteins. The next step in apoptotic signalling by death receptors is the recruitment of initiator procaspase-8 or -10. The death-inducing signalling complex (DISC) forms as a result of this. The DISC catalytically activates caspase-8/-10 and initiates the caspase cascade (MacFarlane 2009). In some cells the activations of caspases 8/10 may be sufficient to carry out cell death but in other cells, caspase 8 may interact with the intrinsic pathway by cleaving Bid which is a member of the Bcl-2 family. The cleavage of this pro-apoptotic protein causes the mitochondrial outer membrane to allow the passage of cytochrome c into the cytosol (Ghobrial et al. 2005). This extrinsic pathway is a rapid and efficient pathway involved in programmed cell death. This described pathway is of particular importance to the immune system with regards to autoimmunity and anti-tumor.
Figure 1 -Apoptosis Pathways.
Source: Nature Reviews Cancer 2, 277-288 (April 2002)
Apoptosis and the developing Immune System
During development the selection of lymphocytes is highly specific. Developing lymphocytes that do not develop a functional B-Cell Receptor (BCR) or T-Cell Receptor (TCR) subsequently result in the loss of apoptosis inhibition signals, therefore are eliminated by apoptosis (Ghobrial et al. 2005). Developing lymphocytes with the functional receptors that react too strongly to self-antigen are considered auto-reactive and are subsequently destroyed by apoptosis. Cytokines are survival factors that prevent apoptosis in immune cells. A study showed that mice with defective cytokine signalling incur excessive loss of developing immune cells by apoptosis resulting in a disorder called; Severe combined Immune Deficiency (SCID) phenotype.
Apoptosis and the Immune System Function
Signalling via the death receptor pathway plays an important role in the immune system function. The extrinsic pathway is involved in the regulation of the adaptive immune system (Fas et al. 2006). This extrinsic death receptor pathway is used by the cytotoxic T cells to kill virally-infected cells and eliminate auto-reactive T cells and redundant immune cells. This pathway is the main apoptotic pathway responsible for tissue homeostasis. An imbalance in cell death/survival homeostasis can subsequently be quite problematic, excessive lymphocyte apoptosis can lead to immunodeficiency and insufficient apoptosis can lead to autoimmunity or lymphoma.
Fas Receptor signalling pathway
Fas ligand is expressed on the surface of activated T cells. Fas ligand binding to Fas receptor initiates apoptosis by a similar mechanism to TNF- alpha, except that in this signalling pathway FADD can be directly recruited to the receptors death domain without prior recruitment of TRADD. This is why this particular pathway is the most commonly used signalling pathway by cells. This signalling pathway plays many important roles in the immune system. One such role of this signalling pathway in the immune system is its major role in the regulation on lymphocyte homeostasis (Strasser, Jost and Nagata 2009). Another critical role of this pathway in the immune system is the killing of infected or damaged cells (Strasser et al. 2009).
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TRAIL Receptor Signalling Pathway
This signalling pathway plays an important role in anti-tumor surveillance. Unlike the other signalling pathways TRAIL has 5 different receptors which it can bind to. TRAILR-4 and 5 are the most important receptors in carrying out its function. TRAIL receptors 1, 2 and OPG are three decoy receptors, simply meaning that TRAIL can bind to these decoy receptors with equal affinity but binding does not induce apoptosis as these receptors like the death domain regions. TRAIL has the efficient ability to induce apoptosis in cancer cells. However it does not significantly induce apoptosis in the majority of normal cells (Audo et al. 2009). The lack of TRAIL signalling results in the proliferation of cancer cells and the formation of tumors. This has lead to studies suggesting that TRAIL is potentially an anti-cancer therapy. (Trauzold et al. 2006) reported that TRAIL had the ability to enhance apoptosis but also could enhance other non-apoptotic signalling pathways and so other therapy conditions are required along with TRAIL to ensure that other non-apoptotic signalling pathways are not activated (Wang 2008). This potential therapy provides advantages over current cancer treatments such as chemotherapy, which works by killing both cancer and healthy cells, leaving patients susceptible to further infections, whereas TRAIL may just target cancer cells and eliminate them by controlled cell death.
TRAIL has also recently been proposed to mediate negative selection of autoreactive thymocytes and to play a role in preventing arthritis.
In summary, the extrinsic pathway plays a very important role in the immune system, in both the development and the function. Impaired apoptosis via the death receptor pathway can result in an imbalance in tissue homeostasis which can ultimately lead to the development of cancer or auto immune diseases.