Death Receptor-Mediated Apoptosis and Lymphocyte Homeostasis
Richard K. Burt, Alberto M. Marmont in Stem Cell Therapy for Autoimmune Disease, 2019
It has been found that genetic deficiencies in apoptosis pathways can lead to developmental abnormalities and disease.12 One of the major breakthroughs in determining the physiological relevance of lymphocyte apoptosis and autoimmune disorders came from the identification of genetic mutations of CD95 (Fas) in Ipr mice and CD95 ligand (FasL) in gld mice.121,122 The Ipr stands for “lymphoproliferative response” and the gld for “generalized lymphoproliferative disease”. In Ipr mice, a transposable element insertion in the 2nd intron of CD95 gene disrupts transcription of the gene while in gld mice, a point mutation in the CD95L gene produces a mutant protein that fails to bind CD95. In both cases, peripheral lymphocytes escape from CD95-mediated cell death. Over their lifetime, these mice develop progressive lymphoadenopathy, splenomegaly, and autoimmune disease.123 These data indicate that death receptor-mediated apoptosis is important for shaping the immune system by limiting lymphocyte accumulation.
Apoptosis and Plaque Vulnerability
Levon Michael Khachigian in High-Risk Atherosclerotic Plaques, 2004
Evidence suggests that VSMC death in vitro can be triggered by interaction with inflammatory cells that express cell surface death ligands or secrete pro-apoptotic cytokines such as TNF-.46,50,51 Moreover, exposure to altered lipid composition (e.g., predominantly oxidized LDL) and external mechanical stress (e.g., shear stress or nitric oxide as a result of alterations in blood flow) can also trigger the deaths of these cells.52–56 Activation of receptors other than those of the death receptor superfamily can also affect VSMC apoptosis. For example, mice that lack the neurotrophin receptor (p75 NTR) demonstrate changes in the regulation of apoptosis following ligation of the left carotid artery. p75 NTR-deficient mice exhibit decreased apoptosis in neointimal smooth muscle cells and three- to fourfold increased development of stenosis when compared with wild type animals.57 Thus, apoptosis regulated via p75 NTR may suppress neointima formation in this model.
Neurological manifestations of West Nile virus
Avindra Nath, Joseph R. Berger in Clinical Neurovirology, 2020
It is known that WNV infection in neurons leads to apoptosis through induction of caspase 3. Mice lacking caspase 3 shows decreased neuronal death and tissue injury [22]. Recent work has elucidated details of the pathways by which this occurs and suggests that it centers around up-regulation of genes involved with death receptor-associated caspase signaling [23]. In a mouse model of WNV infection, activity of death-receptor associated initiator caspase 8 was up-regulated and was associated with downstream cleavage of the Bcl-2 family protein Bid, and subsequent activation of caspase 9. Studies using an ex-vivo mouse brain slice culture model, which allows investigation of brain-intrinsic immune responses in isolation from peripheral immunity, showed that inhibition of caspase 8 decreased virus-induced activation of caspase 3, and led to reduced WNV-associated CNS injury. This occurred in the brain slices that lack infiltrating inflammatory cells and indicate that WNV infection triggers apoptosis independently of lymphocyte presence and activation [23]. In the brain-slice culture, astrocytes and microglia were highly activated, which suggests that local immune responses within the CNS (“neuroinflammation”), while also helping to control the initial stages of viral replication, may also contribute to WNV-mediated CNS tissue injury.
The role of the Fas/FasL signaling pathway in environmental toxicant-induced testicular cell apoptosis: An update
Published in Systems Biology in Reproductive Medicine, 2018
Apoptotic signaling pathways include the mitochondrial pathway, endoplasmic reticulum pathway, and death receptor pathway (Xu et al. 2016). Currently, there are five known death receptors (Ashkenazi and Dixit 1998): Tumor necrosis factor receptor 1 (TNF-R1), Fas, death receptor 3 (DR3), death receptor 4 (DR4), and death receptor 5 (DR5). ‘Death receptor pathway’ refers to a variety of external factors that promote apoptotic agents, i.e., apoptotic signals mediated through different death receptor signaling systems, eventually causing apoptosis (Ashkenazi and Salvesen 2014). Fas/FasL signaling is a key element of the death receptor signaling pathway (Figure 1). Fas and its ligand FasL have a profound effect on the balance of proliferation and apoptosis (Lavrik 2014).The Fas/FasL signaling pathway is one of the major regulatory pathways of apoptosis. FasL induces the formation of the Fas trimer, in which the three death domains (DD) of Fas cluster together to bind to FasL. This Fas trimer recruits and binds to the N-terminal death effector domain (DED) of the cytoplasmic adapter protein, Fas associated death domain (FADD), and transmits the apoptotic signal to procaspase-8. The formation of the death-inducing signaling complex (DISC), which is constituted by the Fas-FasL-FADD-procaspase-8 on the cell membrane, leads to caspase hydrolysis and a series of enzyme-linked reactions. The DNA-degrading enzyme is ultimately activated, which results in degradation of DNA and induces cell apoptosis (Xu et al. 2016) (Figure 1).
The 70-kDa heat shock protein (Hsp70) as a therapeutic target for stroke
Published in Expert Opinion on Therapeutic Targets, 2018
Jong Youl Kim, Yeonseung Han, Jong Eun Lee, Midori A. Yenari
Extrinsic or cell surface mediated mechanisms of apoptosis involve the engagement of death receptors located on the plasma membrane. This is also referred as the ‘death receptor pathway’. Death receptor ligation causes activation of caspase-8 and caspase-10, which in turn can activate effector caspase-3 [51]. Activation of several death receptors (Fas/CD95, TNFR1, and TRAIL receptor) is promoted by ligands of TNF family, including FASL, TNF, LT-α, LT-β, CD40L, LIGHT, RANKL, and TRAIL, many of which are released as part of the inflammatory response to ischemia [52]. FasL is involved in apoptosis by binding to the Fas receptor, triggering recruitment of the cytoplasmic adaptor protein Fas-associated death domain protein (FADD). FADD contains a ‘death effector domain’ at the N terminus which binds to procaspase-8 by interacting with its death effector domain [53]. This complex is referred to as the death-inducing signaling complex (DISC). This signal complex catalyzes the proteolytic cleavage and transactivation of procaspase-8 to generate activated caspase-8 [53]. Caspase-8 activation is followed by activation of caspases−3 and −10 [54].
Ramelteon and mechanism of its restorative effect in an experimental lung disease model
Published in Toxicology Mechanisms and Methods, 2023
İlkay Armağan, Halil Aşcı, Yalçın Erzurumlu, Songül Özkula, Nursel Hasseyid, Duygu Kumbul Doğuç, Gözde Okuyucu, Ahmetcan Varel
A considerable feature of apoptosis is its effects mainly through a kind of serine protease which is known as caspase. A death signal is transmitted via signaling pathways causing to activate the caspases destroying cell. Apoptosis can be initiated by both intrinsic and extrinsic stimuli combined with intrinsic and extrinsic apoptosis pathways (Xu et al. 2019). Cas-8 is a canonical cysteine protease that is needed for the execution and initiation of apoptosis. It is an important factor in programmed cell death induced by death receptor, and it should be activated for this pathway’s functionality (Fianco et al. 2018). The MTX group had significantly higher Cas-8 level indicating that the increase in Cas-8 is associated with apoptosis in inflammatory cells, alveolar, bronchiolar and bronchial epithelial cells. RML treatment, on the other hand, regressed apoptosis by reducing the level of Cas-8 and exhibited antiapoptotic properties. The fact that increasing Cas-8 levels are inversely related to decreasing AQP levels indicates that the AQP levels, especially in cell membranes, decrease along with dying cells. Agents that can prevent inflammation or apoptosis may contribute to the maintenance or increase in AQP levels. At the same time, the observation after routine histochemical examination that the general tissue toxicity findings, including inflammation, observed in the injury group, changed significantly with RML. These histopathological changes support immunohistochemistry and other molecular findings.
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