Molecular Insights into the Mechanism of Necroptosis: The Necrosome as a Potential Therapeutic Target

Chen, Jing; R, Kós; Garssen, Johan; Redegeld, Frank A.

doi:10.3390/cells8121486

Cited by 135 publications

(132 citation statements)

References 105 publications

(136 reference statements)

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“…Mechanically, upon pathogenic stimuli following TBI, TNF-α-induced receptor-interacting protein 1 activation contributes to the formation of the so-called necrosome, a complex necessary for necroptosis [40,41]. And after necroptosis, inflammatory factors released from damaged cells flow into the extracellular space, boosting the neuroinflammation [41][42][43]. All these primary or secondary pathologic mechanisms contribute to cell death, tissue loss, structural and metabolic abnormalities, and an ultimate neurological dysfunction in the patients [15,44].…”

Section: Introductionmentioning

confidence: 99%

Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury

et al. 2020

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Traumatic brain injury (TBI) is one of the leading causes of fatality and disability worldwide. Despite its high prevalence, effective treatment strategies for TBI are limited. Traumatic brain injury induces structural and functional alterations of astrocytes, the most abundant cell type in the brain. As a way of coping with the trauma, astrocytes respond in diverse mechanisms that result in reactive astrogliosis. Astrocytes are involved in the physiopathologic mechanisms of TBI in an extensive and sophisticated manner. Notably, astrocytes have dual roles in TBI, and some astrocyte-derived factors have double and opposite properties. Thus, the suppression or promotion of reactive astrogliosis does not have a substantial curative effect. In contrast, selective stimulation of the beneficial astrocytederived molecules and simultaneous attenuation of the deleterious factors based on the spatiotemporalenvironment can provide a promising astrocyte-targeting therapeutic strategy. In the current review, we describe for the first time the specific dual roles of astrocytes in neuronal plasticity and reconstruction, including neurogenesis, synaptogenesis, angiogenesis, repair of the blood-brain barrier, and glial scar formation after TBI. We have also classified astrocyte-derived factors depending on their neuroprotective and neurotoxic roles to design more appropriate targeted therapies.

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Section: Introductionmentioning

confidence: 99%

Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury

et al. 2020

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“…The mechanisms underlying the necroptosis pathway are mostly elucidated by a model of tumor necrosis factor alpha (TNFα)-induced cell death [ 8 , 9 , 35 , 36 , 37 , 38 ]. The binding of TNF to TNFR1 induces a conformational change in TNFR1 trimers, leading to the recruitment of a multiprotein platform named complex I, which includes RIPK1, TRADD (TNFR-associated death domain), cIAP1 (cellular inhibitor of apoptosis protein 1), cIAP2 and TRAF (TNFR-associated factor)2.…”

Section: Necroptosis Signaling Pathwaymentioning

confidence: 99%

“…Here, we summarize a panel of compounds that targets necroptosis, some of which were successfully experimented with in preclinical and clinical trials [ 8 , 19 , 131 ].…”

Section: Therapeutic Perspectivesmentioning

confidence: 99%

“…Other RIPK1 inhibitors have been developed by GlaxoSmithKline, among which GSK2982772 is currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis [ 137 , 138 ] and GSK3145095 has terminated the phase I clinical trials for solid tumors [ 8 ].…”

Section: Therapeutic Perspectivesmentioning

confidence: 99%

“…The receptor-interacting protein kinase 1 (RIPK1) and 3 (RIPK3), as well as their target, the mixed lineage kinase domain-like protein (MLKL), are required to initiate necroptosis [ 5 , 6 , 7 ]. Necroptosis is associated with various human diseases including ischemic reperfusion injury, inflammatory, neurodegenerative, infectious, autoimmune diseases and cancer [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. Recently, necroptosis has been also involved in mediating organ rejection in cardiac and renal allografts [ 8 , 12 , 19 , 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

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Necroptosis in Intestinal Inflammation and Cancer: New Concepts and Therapeutic Perspectives

et al. 2020

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Necroptosis is a caspases-independent programmed cell death displaying intermediate features between necrosis and apoptosis. Albeit some physiological roles during embryonic development such tissue homeostasis and innate immune response are documented, necroptosis is mainly considered a pro-inflammatory cell death. Key actors of necroptosis are the receptor-interacting-protein-kinases, RIPK1 and RIPK3, and their target, the mixed-lineage-kinase-domain-like protein, MLKL. The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. Altered necroptosis at the intestinal epithelium leads to uncontrolled microbial translocation and deleterious inflammation. Indeed, necroptosis plays a role in many disease conditions and inhibiting necroptosis is currently considered a promising therapeutic strategy. In this review, we focus on the molecular mechanisms of necroptosis as well as its involvement in human diseases. We also discuss the present developing therapies that target necroptosis machinery.

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Mendelian diseases of dysregulated canonical NF-κB signaling: From immunodeficiency to inflammation

Schnappauf

Aksentijevich

2020

Journal of Leukocyte Biology

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NF-B is a master transcription factor that activates the expression of target genes in response to various stimulatory signals. Activated NF-B mediates a plethora of diverse functions including innate and adaptive immune responses, inflammation, cell proliferation, and NF-B is regulated through interactions with I B inhibitory proteins, which are in turn regulated by the inhibitor of B kinase (IKK) complex. Together, these 3 components form the core of the NF-B signalosomes that have cell-specific functions which are dependent on the interactions with other signaling molecules and pathways. The activity of NF-B pathway is also regulated by a variety of post-translational modifications including phosphorylation and ubiquitination by Lys63, Met1, and Lys48 ubiquitin chains. The physiologic role of NF-B is best studied in the immune system due to discovery of many human diseases caused by pathogenic variants in various proteins that constitute the NF-B pathway. These disease-causing variants can act either as gain-of-function (GoF) or loss-of-function (LoF) and depending on the function of mutated protein, can cause either immunodeficiency or systemic inflammation. Typically, pathogenic missense variants act as GoF and they lead to increased activity in the pathway. LoF variants can be inherited as recessive or dominant alleles and can cause either a decrease or an increase in pathway activity. Dominantly inherited LoF variants often result in haploinsufficiency of inhibitory proteins. Here, we review human Mendelian immunologic diseases, which results from mutations in different molecules in the canonical NF-B pathway and surprisingly present with a continuum of clinical features including immunodeficiency, atopy, autoimmunity, and autoinflammation.

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Molecular Insights into the Mechanism of Necroptosis: The Necrosome as a Potential Therapeutic Target

Cited by 135 publications

References 105 publications

Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury

Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury

Necroptosis in Intestinal Inflammation and Cancer: New Concepts and Therapeutic Perspectives

Mendelian diseases of dysregulated canonical NF-κB signaling: From immunodeficiency to inflammation

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