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Lily Dara, Zhang-Xu Liu, Neil Kaplowitz
Hepatocyte death, which can be apoptosis or necrosis depending on the context, is a prominent feature of liver disease. The lectin concanavalin A (ConA) activates immune cells, resulting in inflammatory liver injury and hepatocyte necrosis. In this issue of the JCI, Günther et al. demonstrate that the pseudokinase mixed lineage kinase domain-like protein (MLKL) participates in hepatocyte death in ConA injury and that MLKL-mediated death is independent of the receptor-interacting protein kinase RIPK3. RIPK3 was absent in hepatocytes, and MLKL-deficient mice, but not RIPK3-deficient mice, were protected from ConA-induced liver injury...
October 17, 2016: Journal of Clinical Investigation
Claudia Günther, Gui-Wei He, Andreas E Kremer, James M Murphy, Emma J Petrie, Kerstin Amann, Peter Vandenabeele, Andreas Linkermann, Christopher Poremba, Ulrike Schleicher, Christin Dewitz, Stefan Krautwald, Markus F Neurath, Christoph Becker, Stefan Wirtz
Although necrosis and necroinflammation are central features of many liver diseases, the role of programmed necrosis in the context of inflammation-dependent hepatocellular death remains to be fully determined. Here, we have demonstrated that the pseudokinase mixed lineage kinase domain-like protein (MLKL), which plays a key role in the execution of receptor-interacting protein (RIP) kinase-dependent necroptosis, is upregulated and activated in human autoimmune hepatitis and in a murine model of inflammation-dependent hepatitis...
October 18, 2016: Journal of Clinical Investigation
Roshan J Thapa, Justin P Ingram, Katherine B Ragan, Shoko Nogusa, David F Boyd, Asiel A Benitez, Haripriya Sridharan, Rachelle Kosoff, Maria Shubina, Vanessa J Landsteiner, Mark Andrake, Peter Vogel, Luis J Sigal, Benjamin R tenOever, Paul G Thomas, Jason W Upton, Siddharth Balachandran
Influenza A virus (IAV) is an RNA virus that is cytotoxic to most cell types in which it replicates. IAV activates the host kinase RIPK3, which induces cell death via parallel pathways of necroptosis, driven by the pseudokinase MLKL, and apoptosis, dependent on the adaptor proteins RIPK1 and FADD. How IAV activates RIPK3 remains unknown. We report that DAI (ZBP1/DLM-1), previously implicated as a cytoplasmic DNA sensor, is essential for RIPK3 activation by IAV. Upon infection, DAI recognizes IAV genomic RNA, associates with RIPK3, and is required for recruitment of MLKL and RIPK1 to RIPK3...
October 8, 2016: Cell Host & Microbe
Simone Wicki, Ursina Gurzeler, W Wei-Lynn Wong, Philipp J Jost, Daniel Bachmann, Thomas Kaufmann
Neutrophils are essential players in the first-line defense against invading bacteria and fungi. Besides its antiapoptotic role, the inhibitor of apoptosis protein (IAP) family member X-linked IAP (XIAP) has been shown to regulate innate immune signaling. Whereas the role of XIAP in innate signaling pathways is derived mostly from work in macrophages and dendritic cells, it is not known if and how XIAP contributes to these pathways in neutrophils. Here we show that in response to bacterial lipopolysaccharides (LPS), mouse neutrophils secreted considerable amounts of tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β) and, in accordance with earlier reports, XIAP prevented LPS-induced hypersecretion of IL-1β also in neutrophils...
October 13, 2016: Cell Death & Disease
Ulrike Höckendorf, Monica Yabal, Philipp J Jost
No abstract text is available yet for this article.
October 11, 2016: Cell Cycle
Ryodai Shindo, Soh Yamazaki, Masaki Ohmuraya, Kimi Araki, Hiroyasu Nakano
Cellular FLICE-inhibitory protein (cFLIP) is a catalytically inactive homolog of the initiator caspase, caspase 8 and blocks apoptosis through binding to caspase 8. Human CFLAR gene encodes two proteins, a long form cFLIP (cFLIPL) and a short form cFLIP (cFLIPs) due to an alternative splicing. Recent studies have shown that expression of cFLIPs, but not cFLIPL promotes programmed necrosis (also referred to as necroptosis) in an immortalized human keratinocyte cell line, HaCaT. Here, we found that expression of cFLIPs similarly promoted necroptosis in immortalized fibroblasts...
October 6, 2016: Biochemical and Biophysical Research Communications
Lianshuang Zhang, Jialiu Wei, Lihua Ren, Jin Zhang, Man Yang, Li Jing, Ji Wang, Zhiwei Sun, Xianqing Zhou
Endosulfan, an organochlorine pesticide, was found in human blood, and its possible cardiovascular toxicity has been suggested. However, the mechanism about endothelial cell injuries induced by endosulfan has remained unknown. In the present study, human umbilical vein endothelial cells (HUVECs) were chosen to explore the toxicity mechanism and were treated with 0, 1, 6, and 12 μg/mL(-1) endosulfan for 24 h, respectively. The results showed that exposure to endosulfan could inhibit the cell viability, increase the release of lactate dehydrogenase (LDH), damage the ultrastructure, and lead to apoptosis and necroptosis in HUVECs...
October 5, 2016: Environmental Science and Pollution Research International
Chelsea Corradetti, Neelakshi R Jog, Stefania Gallucci, Michael Madaio, Siddharth Balachandran, Roberto Caricchio
Immune mediated nephropathy is one of the most serious manifestations of lupus and is characterized by severe inflammation and necrosis that, if untreated, eventually leads to renal failure. Although lupus has a higher incidence in women, both sexes can develop lupus glomerulonephritis; nephritis in men develops earlier and is more severe than in women. It is therefore important to understand the cellular and molecular mechanisms mediating nephritis in each sex. Previous work by our lab found that the absence or pharmacological inhibition of Poly [ADP-ribose] polymerase 1 (PARP-1), an enzyme involved in DNA repair and necrotic cell death, affects only male mice and results in milder nephritis, with less in situ inflammation, and diminished incidence of necrotic lesions, allowing for higher survival rates...
2016: PloS One
Deepika Arora, Mohammed Haris Siddiqui, Pradeep Kumar Sharma, Yogeshwer Shukla
Deltamethrin (DLM), a synthetic pyrethroid insecticide, is used all over the world for indoor and field pest management. In the present study, we investigated the elicited pathogenesis of DLM-induced hepatotoxicity in rat primary hepatocytes. DLM-induced cell death was accompanied with increased ROS generation, decreased mitochondrial membrane potential and G2/M arrest. Pre-treatment with N-acetyl cysteine/butylated hydroxyanisole/IM54 could partly rescue hepatocytes suggesting that ROS might play a role in DLM-induced toxicity...
October 14, 2016: Biochemical and Biophysical Research Communications
Jo Suda, Lily Dara, Luoluo Yang, Mariam Aghajan, Yong Song, Neil Kaplowitz, Zhang-Xu Liu
Receptor-interacting protein kinase (RIPK)1 has an essential role in the signaling pathways triggered by death receptors through activation of NF-κB and regulation of caspase-dependent apoptosis and RIPK3/mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis. We examined the effect of RIPK1 antisense knockdown on immune-mediated liver injury in C57BL/6 mice caused by α-galactosylceramide (αGalCer), a specific activator for invariant NKT cells. We found that knockdown of RIPK1 markedly exacerbated αGalCer-mediated liver injury and induced lethality...
September 7, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Luiz G B Siqueira, Peter J Hansen
We tested whether gene expression of the bovine morula is modified by CSF2 in a sex-dependent manner and if sex determines the effect of CSF2 on competence of embryos to become blastocysts. Embryos were produced in vitro using X- or Y-sorted semen and treated at day 5 of culture with 10 ng/ml bovine CSF2 or control. In experiment 1, morulae were collected at day 6 and biological replicates (n=8) were evaluated for transcript abundance of 90 genes by RT-qPCR using the Fluidigm® Delta GeneTM assay. Expression of more than one third (33 of 90) of genes examined was affected by sex...
September 6, 2016: Reproduction: the Official Journal of the Society for the Study of Fertility
Long Pan, Dun-Chen Yao, Yu-Zhong Yu, Sheng-Jie Li, Bing-Jun Chen, Gui-He Hu, Chang Xi, Zi-Hui Wang, Hong-Yan Wang, Jian-Hua Li, Yong-Sheng Tu
Necroptosis is a recently discovered necrotic cell death which is regulated by receptor interacting protein kinase 1 (RIPK1) and RIPK3 under the stimulus of death signal and can be inhibited by necrostatin-1 (Nec-1) specifically. Therefore, the aim was to investigate the role of necroptosis in a rat model of acute respiratory distress syndrome (ARDS) induced by oleic acid (OA) and assess the effect of Nec-1 on lung injury in ARDS. Our results found that RIPK1, RIPK3 and mixed lineage kinase domain-like protein (MLKL) were abundantly expressed in rat lung tissues of OA-induced ARDS...
September 30, 2016: Biochemical and Biophysical Research Communications
Cunxian Fan, Wenjuan Pu, Xiaoxia Wu, Xixi Zhang, Lingjuan He, Bin Zhou, Haibing Zhang
No abstract text is available yet for this article.
2016: Cell Death & Disease
Alessandra Pescatore, Elio Esposito, Peter Draber, Henning Walczak, Matilde Valeria Ursini
Incontinentia Pigmenti (IP) is a rare X-linked disease characterized by early male lethality and multiple abnormalities in heterozygous females. IP is caused by NF-κB essential modulator (NEMO) mutations. The current mechanistic model suggests that NEMO functions as a crucial component mediating the recruitment of the IκB-kinase (IKK) complex to tumor necrosis factor receptor 1 (TNF-R1), thus allowing activation of the pro-survival NF-κB response. However, recent studies have suggested that gene activation and cell death inhibition are two independent activities of NEMO...
2016: Cell Death & Disease
J Hanus, C Anderson, D Sarraf, J Ma, S Wang
Age-related macular degeneration (AMD) is a degenerative disease of the retina and the leading cause of blindness in the elderly in developed countries. The late stage of dry AMD, or geographic atrophy (GA), is characterized by extensive retinal pigment epithelium (RPE) degeneration. The underlying molecular mechanism for RPE cell death in GA remains unclear. Our previous study has established that RPE cells die predominantly from necroptosis in response to oxidative stress in vitro. Here, we extend our study and aim to characterize the nature of RPE cell death in response to sodium iodate (NaIO3) in vitro and in a NaIO3-induced retina degeneration mouse model...
2016: Cell Death Discovery
Jiraporn Ousingsawat, Inês Cabrita, Podchanart Wanitchakool, Lalida Sirianant, Stefan Krautwald, Andreas Linkermann, Rainer Schreiber, Karl Kunzelmann
Activated receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain like (MLKL) are essential components of the necroptotic pathway. Phosphorylated MLKL (pMLKL) is thought to induce membrane leakage, leading to cell swelling and disintegration of the cell membrane. However, the molecular identity of the necroptotic membrane pore remains unclear, and the role of pMLKL for membrane permeabilization is currently disputed. We observed earlier that the phospholipid scramblase and ion channel TMEM16F/anoctamin 6 cause large membrane currents, cell swelling, and cell death when activated by a strong increase in intracellular Ca(2+)...
August 17, 2016: Cellular and Molecular Life Sciences: CMLS
Kipyegon Kitur, Sarah Wachtel, Armand Brown, Matthew Wickersham, Franklin Paulino, Hernán F Peñaloza, Grace Soong, Susan Bueno, Dane Parker, Alice Prince
Staphylococcus aureus triggers inflammation through inflammasome activation and recruitment of neutrophils, responses that are critical for pathogen clearance but are associated with substantial tissue damage. We postulated that necroptosis, cell death mediated by the RIPK1/RIPK3/MLKL pathway, would function to limit pathological inflammation. In models of skin infection or sepsis, Mlkl-/- mice had high bacterial loads, an inability to limit interleukin-1b (IL-1b) production, and excessive inflammation. Similarly, mice treated with RIPK1 or RIPK3 inhibitors had increased bacterial loads in a model of sepsis...
August 23, 2016: Cell Reports
Silvia Alvarez-Diaz, Christopher P Dillon, Najoua Lalaoui, Maria C Tanzer, Diego A Rodriguez, Ann Lin, Marion Lebois, Razq Hakem, Emma C Josefsson, Lorraine A O'Reilly, John Silke, Warren S Alexander, Douglas R Green, Andreas Strasser
The kinases RIPK1 and RIPK3 and the pseudo-kinase MLKL have been identified as key regulators of the necroptotic cell death pathway, although a role for MLKL within the whole animal has not yet been established. Here, we have shown that MLKL deficiency rescued the embryonic lethality caused by loss of Caspase-8 or FADD. Casp8(-/-)Mlkl(-/-) and Fadd(-/-)Mlkl(-/-) mice were viable and fertile but rapidly developed severe lymphadenopathy, systemic autoimmune disease, and thrombocytopenia. These morbidities occurred more rapidly and with increased severity in Casp8(-/-)Mlkl(-/-) and Fadd(-/-)Mlkl(-/-) mice compared to Casp8(-/-)Ripk3(-/-) or Fadd(-/-)Ripk3(-/-) mice, respectively...
September 20, 2016: Immunity
Ulrike Höckendorf, Monica Yabal, Philipp J Jost
No abstract text is available yet for this article.
August 10, 2016: Oncotarget
Xixi Zhang, Cunxian Fan, Haiwei Zhang, Qun Zhao, Yongbo Liu, Chengxian Xu, Qun Xie, Xiaoxia Wu, Xianjun Yu, Jianke Zhang, Haibing Zhang
MLKL, a key component downstream of RIPK3, is suggested to be a terminal executor of necroptosis. Genetic studies have revealed that Ripk3 ablation rescues embryonic lethality in Fadd- or Caspase-8-deficient mice. Given that RIPK3 has also been implicated in non-necroptotic pathways including apoptosis and inflammatory signaling, it remains unclear whether the lethality in Fadd(-/-) mice is indeed caused by necropotosis. Here, we show that genetic deletion of Mlkl rescues the developmental defect in Fadd-deficient mice and that Fadd(-/-)Mlkl(-/-) mice are viable and fertile...
September 20, 2016: Cell Reports
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