[Show abstract][Hide abstract] ABSTRACT: Excessive acetaminophen (APAP) use is one of the most common causes of acute liver failure. Various types of cell death in the damaged liver are linked to APAP-induced hepatotoxicity, and, of these, necrotic cell death of hepatocytes has been shown to be involved in disease pathogenesis. Until recently, necrosis was commonly considered to be a random and unregulated form of cell death; however, recent studies have identified a previously unknown form of programmed necrosis called receptor-interacting protein kinase (RIPK)-dependent necrosis (or necroptosis), which is controlled by the kinases RIPK1 and RIPK3. Although RIPK-dependent necrosis has been implicated in a variety of disease states, including atherosclerosis, myocardial organ damage, stroke, ischemia-reperfusion injury, pancreatitis, and inflammatory bowel disease. However its involvement in APAP-induced hepatocyte necrosis remains elusive. Here, we showed that RIPK1 phosphorylation, which is a hallmark of RIPK-dependent necrosis, was induced by APAP, and the expression pattern of RIPK1 and RIPK3 in the liver overlapped with that of CYP2E1, whose activity around the central vein area has been demonstrated to be critical for the development of APAP-induced hepatic injury. Moreover, a RIPK1 inhibitor ameliorated APAP-induced hepatotoxicity in an animal model, which was underscored by significant suppression of the release of hepatic enzymes and cytokine expression levels. RIPK1 inhibition decreased reactive oxygen species levels produced in APAP-injured hepatocytes, whereas CYP2E1 expression and the depletion rate of total glutathione were unaffected. Of note, RIPK1 inhibition also conferred resistance to oxidative stress in hepatocytes. These data collectively demonstrated a RIPK-dependent necrotic mechanism operates in the APAP-injured liver and inhibition of this pathway may be beneficial for APAP-induced fulminant hepatic failure.
[Show abstract][Hide abstract] ABSTRACT: The vertebrate immune system is highly dependent on cell death for efficient responsiveness to microbial pathogens and oncogenically transformed cells. Cell death pathways are vital to the function of many immune cell types during innate, humoral and cellular immune responses. In addition, cell death regulation is imperative for proper adaptive immune self-tolerance and homeostasis. While apoptosis has been found to be involved in several of these roles in immunity, recent data demonstrate that alternative cell death pathways are required. Here, we describe the involvement of a programmed form of cellular necrosis called “necroptosis” in immunity. We consider the signaling pathways that promote necroptosis downstream of death receptors, type I transmembrane proteins of the tumor necrosis factor (TNF) receptor family. The involvement of necroptotic signaling through a “RIPoptosome” assembled in response to innate immune stimuli or genotoxic stress is described. We also characterize the induction of necroptosis following antigenic stimulation in T cells lacking caspase-8 or FADD function. While necroptotic signaling remains poorly understood, it is clear that this pathway is an essential component to effective vertebrate immunity.
Seminars in Cell and Developmental Biology 11/2014; · 6.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Necroptosis is a form of regulated necrosis that can be activated by ligands of death receptors and stimuli that induce the expression of death receptor ligands under apoptotic deficient conditions. Activation of necroptosis by ligands of death receptors requires the kinase activity of RIP1, which mediates the activation of RIP3 and MLKL, two critical downstream mediators of necroptosis. Blocking the kinase activity of RIP1, a key druggable target in the necroptosis pathway, by necrostatins inhibits the activation of necroptosis and allows cell survival and proliferation in the presence of death receptor ligands. The activation of necroptosis is modulated by different forms of ubiquitination, including K63, linear and K48 ubiquitination, as well as phosphorylation of RIP1, RIP3 and MLKL. Necroptosis is suppressed by caspase-8/FADD-mediated apoptosis. Deficiency in caspase-8 and FADD leads to embryonic lethality, tissue degeneration and inflammation which can be suppressed by inhibition of RIP1 kinase and RIP3. On the other hand, the lack of RIP3 kinase activity leads to early embryonic lethality which can be suppressed by the loss of caspase-8, suggesting that although the kinase activity of RIP3 is involved in mediating necroptosis, the basal activity of RIP3 kinase may be required for suppressing caspase-8 mediated apoptosis. Necroptosis as well as RIP1- and RIP3-mediated inflammatory response have been implicated in mediating multiple human diseases including TNF-mediated hypothermia and systemic inflammation, ischemic reperfusion injury, neurodegeneration, Gaucher's disease, progressive atherosclerotic lesions, etc. Targeting RIP1 kinase may provide therapeutic benefits for the treatment of human diseases characterized by necrosis and inflammation.
Seminars in Cell and Developmental Biology 01/2014; · 6.20 Impact Factor
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