Necroptosis: A Novel Cell Death Modality and Its Potential Relevance for Critical Care Medicine

Moreno‐González, Gabriel; Vandenabeele, Peter; Krysko, Dmitri V.

doi:10.1164/rccm.201510-2106ci

Cited by 74 publications

(56 citation statements)

References 141 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TLR3, TLR4, and the z‐DNA sensor DNA‐dependent activator of IFN‐regulatory factors [DAI]), and by activating T‐cell receptors and type I and type II IFNs. One of the best‐characterized signaling mechanisms of necroptosis is the binding of TNF to TNFR1, which induces the formation of several protein complexes involved in pro‐inflammatory and survival signaling (complex I), apoptosis (complex IIa and IIb) and necroptosis (complex IIc) (for a review see references). Notably, triggering TNFR1 leads to the induction of necroptosis only when apoptosis signaling is blocked (e.g.…”

Section: Necroptosis: Molecular Mechanisms In Briefmentioning

confidence: 99%

“…However, a regulated type of necrosis (necroptosis) has been revealed thanks to the identification of chemical inhibitors of necrotic cell death (necrostatins), which underline its regulated nature (Table ) . It has been established that necroptosis is different from apoptosis and that it is regulated by receptor interacting protein kinase‐1 (RIPK1), RIPK3, and mixed lineage kinase domain‐like (MLKL) . Other necrotic cell death modalities that come under the umbrella term of regulated necrosis are ferroptosis and pyroptosis (Table ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Necroptotic cell death in anti‐cancer therapy

Krysko

Aaes

Kagan

et al. 2017

Immunological Reviews

Self Cite

141

103

View full text Add to dashboard Cite

Necroptosis is one the best-characterized forms of regulated necrosis. Necroptosis is mediated by the kinase activities of receptor interacting protein kinase-1 and receptor interacting protein kinase-3, which eventually lead to the activation of mixed lineage kinase domain-like. Necroptosis is characterized by rapid permeabilization of the plasma membrane, which is associated with the release of the cell content and subsequent exposure of damage-associated molecular patterns (DAMPs) and cytokines/chemokines. This release underlies the immunogenic nature of necroptotic cancer cells and their ability to induce efficient anti-tumor immunity. Triggering necroptosis has become especially important in experimental cancer treatments as an alternative to triggering apoptosis because one of the hallmarks of cancer is the blockade or evasion of apoptosis. In this review, we discuss recent advances in necroptosis research and the functional consequences of necroptotic cancer cell death, with focus on its immunogenicity and its role in the activation of anti-tumor immunity. Next, we discuss the molecular mechanisms of phosphatidylserine exposure during necroptosis and its role in the recognition of necroptotic cells. We also highlight the complex role of the necroptotic pathway in tumor promotion and suppression and in metastasis. Future studies will show whether necroptosis is truly a better strategy to overcome apoptosis resistance and provide the insights needed for development of novel treatment strategies for cancer.

show abstract

Section: Necroptosis: Molecular Mechanisms In Briefmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Necroptotic cell death in anti‐cancer therapy

Krysko

Aaes

Kagan

et al. 2017

Immunological Reviews

Self Cite

141

103

View full text Add to dashboard Cite

show abstract

“…However, apoptosis is a programmed cell death modality, generally triggered by physiological processes, whereas necrosis is an uncontrolled and accidental cell death modality triggered by pathological processes. Necroptosis, a novel cell death modality, involves the loss of membrane integrity and occurs by a programmable mechanism with a characteristic necrotic cell death phenotype [10-13]. Necroptosis is initiated by the activation of receptor interacting protein (RIP) kinases and mixed-lineage kinase domain-like protein (MLKL).…”

Section: Introductionmentioning

confidence: 99%

Necroptosis Contributes to Urban Particulate Matter-Induced Airway Epithelial Injury

Luo

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Necroptosis, a form of programmed necrosis, is involved in the pathologic process of several kinds of pulmonary diseases. However, the role of necroptosis in particulate matter (PM)–induced pulmonary injury remains unclear. The objective of this study is to investigate the involvement of necroptosis in the pathogenesis of PM-induced toxic effects in pulmonary inflammation and mucus hyperproduction, both in vitro and in vivo. Methods: PM was administered into human bronchial epithelial (HBE) cells or mouse airways, and the inflammatory response and mucus production were assessed. The mRNA expressions of IL6, IL8 and MUC5AC in HBE cells and Cxcl1, Cxcl2, and Gm-csf in the lung tissues were detected by quantitative real-time RT-PCR. The secreted protein levels of IL6 and IL8 in culture supernatants and Cxcl1, Cxcl2, and Gm-csf in bronchoalveolar lavage fluid (BALF) were detected by enzyme-linked immunosorbent assay (ELISA). We used Western blot to measure the protein expressions of necroptosis-related proteins (RIPK1, RIPK3, and Phospho-MLKL), NF-κB (P65 and PP65), AP-1 (P-c-Jun and P-c-Fos) and MUC5AC. Cell necrosis and mitochondrial ROS were detected using flow cytometry. In addition, pathological changes and scoring of lung tissue samples were monitored using hemoxylin and eosin (H&E), periodic acid-schiff (PAS) and immunohistochemistry staining. Results: Our study showed that PM exposure induced RIP and MLKL-dependent necroptosis in HBE cells and in mouse lungs. Managing the necroptosis inhibitor Necrostatin-1 (Nec-1) and GSK’872, specific molecule inhibitors of necroptosis, markedly reduced PM-induced inflammatory cytokines, e.g., IL6 and IL8, and MUC5AC in HBE cells. Similarly, administering Nec-1 significantly reduced airway inflammation and mucus hyperproduction in PM-exposed mice. Mechanistically, we found PM–induced necroptosis was mediated by mitochondrial reactive oxygen species-dependent early growth response gene 1, which ultimately promoted inflammation and mucin expression through nuclear factor κB and activator protein-1 pathways, respectively. Conclusions: Our results demonstrate that necroptosis is involved in the pathogenesis of PM–induced pulmonary inflammation and mucus hyperproduction, and suggests that it may be a novel target for treatment of airway disorders or disease exacerbations with airborne particulate pollution.

show abstract

“…It has been shown to have pathological consequences in some models of infection and ischemic injury [1], but can be beneficial in specific types of bacterial infection [2]. The hallmark of necroptotic cell death is the involvement of the necrosome kinases, receptor interacting protein kinases 1 (RIPK1) and 3 (RIPK3) and the mixed lineage kinase like (MLKL) protein [1, 3, 4]. Phosphorylation of RIPK1 leads to recruitment and activation of RIPK3, recruitment to the plasma membrane, MLKL oligomerization, followed by membrane permeabilization [1, 4].…”

mentioning

confidence: 99%

“…The hallmark of necroptotic cell death is the involvement of the necrosome kinases, receptor interacting protein kinases 1 (RIPK1) and 3 (RIPK3) and the mixed lineage kinase like (MLKL) protein [1, 3, 4]. Phosphorylation of RIPK1 leads to recruitment and activation of RIPK3, recruitment to the plasma membrane, MLKL oligomerization, followed by membrane permeabilization [1, 4]. Like the other cell death pathways the kinases that activate necroptosis are highly regulated and linked to the expression of the caspases that function in apoptosis [3].…”

mentioning

confidence: 99%