RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury

Newton, Kim; Dugger, Debra L.; Maltzman, Allie; Greve, JW; Hedehus, M; Martin-McNulty, Baby; Carano, Richard A.D.; Cao, Tingyi; Bruggen, Nick van; Bernstein, Lori R.; Lee, W P; Wu, Xiaoxia; DeVoss, Jason; Zhang, J; Jeet, Surinder; Peng, Ivan; McKenzie, Brent; Roose‐Girma, Merone; Caplazi, Patrick; Diehl, Louis F.; Webster, Joshua D.; Vucic, Domagoj

doi:10.1038/cdd.2016.46

Cited by 395 publications

(452 citation statements)

References 59 publications

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“…Inflammation driven by necroptotic signaling is not necessarily dependent on MLKL killing, but can instead be caused by activation of RIP kinases (42) or through MLKL-activation of NLRP3, driving cytokine secretion (17)(18)(19). Our results indicate that MLKL-induced NLRP3 activity and IL-1β secretion, not necroptotic DAMP release, is the dominant activator of NF-κB signaling in healthy bystander cells.…”

Section: Discussionmentioning

confidence: 76%

Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner

Conos

Chen

Nardo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

380

318

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Necroptosis is a physiological cell suicide mechanism initiated by receptor-interacting protein kinase-3 (RIPK3) phosphorylation of mixed-lineage kinase domain-like protein (MLKL), which results in disruption of the plasma membrane. Necroptotic cell lysis, and resultant release of proinflammatory mediators, is thought to cause inflammation in necroptotic disease models. However, we previously showed that MLKL signaling can also promote inflammation by activating the nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome to recruit the adaptor protein apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) and trigger caspase-1 processing of the proinflammatory cytokine IL-1β. Here, we provide evidence that MLKL-induced activation of NLRP3 requires (i) the death effector four-helical bundle of MLKL, (ii) oligomerization and association of MLKL with cellular membranes, and (iii) a reduction in intracellular potassium concentration. Although genetic or pharmacological targeting of NLRP3 or caspase-1 prevented MLKLinduced IL-1β secretion, they did not prevent necroptotic cell death. Gasdermin D (GSDMD), the pore-forming caspase-1 substrate required for efficient NLRP3-triggered pyroptosis and IL-1β release, was not essential for MLKL-dependent death or IL-1β secretion. Imaging of MLKL-dependent ASC speck formation demonstrated that necroptotic stimuli activate NLRP3 cell-intrinsically, indicating that MLKL-induced NLRP3 inflammasome formation and IL-1β cleavage occur before cell lysis. Furthermore, we show that necroptotic activation of NLRP3, but not necroptotic cell death alone, is necessary for the activation of NF-κB in healthy bystander cells. Collectively, these results demonstrate the potential importance of NLRP3 inflammasome activity as a driving force for inflammation in MLKLdependent diseases.aspase-dependent apoptotic cell death is required for mammalian development and the prevention of autoimmune and neoplastic diseases. Programmed cell death can also act to eliminate pathogen-infected cells, with recent studies highlighting how targeted apoptosis-inducing anticancer compounds can treat viral and intracellular bacterial infections (1, 2). On the other hand, the recently characterized caspase-independent necroptotic cell death pathway is dispensable for organism development but, like apoptosis, can be triggered to kill cells harboring pathogenic microbes (3). A number of studies have also reported how pathological activation of necroptotic signaling may contribute to diverse disease states, such as ischemia-reperfusion injury, atherosclerosis, and liver disease, presumably through cell death and the release of proinflammatory mediators (4).The execution of necroptosis is dependent on receptor interacting serine-threonine protein kinase 3 (RIPK3) phosphorylation of mixed-lineage kinase domain-like protein (MLKL), and MLKL's association with, and disruption of, plasma membrane integrity (5).In the absence of caspase activit...

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Section: Discussionmentioning

confidence: 76%

Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner

Conos

Chen

Nardo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

380

318

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“…Although necrosis is observed in a variety of pathophysiological processes, traditional necrosis is considered unregulated. However, recent studies have confirmed the characteristics of necrosis, known as necroptosis in mouse models of inflammation and ischemia-reperfusion injury [98]. Necroptosis is a form of programmed cell death that is controlled by death signals and displays a death pattern like that of necrosis [98].…”

Section: Necrosis and Necroptosismentioning

confidence: 99%

“…However, recent studies have confirmed the characteristics of necrosis, known as necroptosis in mouse models of inflammation and ischemia-reperfusion injury [98]. Necroptosis is a form of programmed cell death that is controlled by death signals and displays a death pattern like that of necrosis [98]. Local ischemia is caused by obstruction of blood flow to tissue, resulting in a limited supply of oxygen and nutrients, which if prolonged, can impair energy metabolism and cell death [99].…”

Section: Necrosis and Necroptosismentioning

confidence: 99%

Current Mechanistic Concepts in Ischemia and Reperfusion Injury

Yiang

Liao

et al. 2018

Cell Physiol Biochem

1,020

728

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Ischemia-reperfusion injury is associated with serious clinical manifestations, including myocardial hibernation, acute heart failure, cerebral dysfunction, gastrointestinal dysfunction, systemic inflammatory response syndrome, and multiple organ dysfunction syndrome. Ischemia-reperfusion injury is a critical medical condition that poses an important therapeutic challenge for physicians. In this review article, we present recent advances focusing on the basic pathophysiology of ischemia-reperfusion injury, especially the involvement of reactive oxygen species and cell death pathways. The involvement of the NADPH oxidase system, nitric oxide synthase system, and xanthine oxidase system are also described. When the blood supply is re-established after prolonged ischemia, local inflammation and ROS production increase, leading to secondary injury. Cell damage induced by prolonged ischemia-reperfusion injury may lead to apoptosis, autophagy, necrosis, and necroptosis. We highlight the latest mechanistic insights into reperfusion-injury-induced cell death via these different processes. The interlinked signaling pathways of cell death could offer new targets for therapeutic approaches. Treatment approaches for ischemia-reperfusion injury are also reviewed. We believe that understanding the pathophysiology ischemia-reperfusion injury will enable the development of novel treatment interventions.

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“…Lactate is released from cells when glycolytic activity exceeds mitochondrial respiration and can occur in hypoxic as well as normoxic conditions (aerobic glycolysis) (7,8). Lactate-producing aerobic glycolysis takes place in the developing brain (9,10), suggesting that lactate signaling could play a role in glial development and neurogenesis (11). Here we have used HCAR1 KO mice, organotypic brain slice cultures, and immunohistochemistry to examine the role of HCAR1 in the development and survival of neurons and oligodendrocytes in normal conditions and hypoglycemia.…”

Section: T03-022bmentioning

confidence: 99%

GLIA Edinburgh 2017: Abstracts Oral Presentations, Posters, Indexes

2017

Glia

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The chronic inflammatory demyelinating disease multiple sclerosis is characterized by multifocal demyelinating lesions, loss of oligodendrocytes (OLG) and subsequent axonal damage. Remyelination occurs in MS lesions and requires proliferation, migration and differentiation of adult oligodendroglial progenitor cells (OPCs) into mature, myelinating oligodendrocytes. It has been shown that in acute lesions OPCs accumulate at the lesion border and fail to migrate sufficiently into demyelinated lesion areas. Therefore, promotion of the migratory capacity of OPCs into demyelinated areas could be a promising target of new therapy strategies to enhance remyelination. Furthermore, differences between oligodendroglial progenitor cell populations from different CNS locations have been recently emerged; however it is unclear whether this contributes to the variable extent of remyelination observed in MS lesions localized in different CNS regions. We used primary OPCs isolated from either cerebrum or spinal cord using the panning method. In our cultures we observed a significant and reproducible difference in the migratory capacity of OPCs originating from either cerebrum (cOPC) or spinal cord (scOPC) indicating a cell intrinsic mechanism of migratory capability. To date, it is postulated that OPC migration is regulated by complex interactions of inand extrinsic factors. Under the same environmental conditions in vitro, undirected as well as directed migration towards a PDGF gradient is strongly increased in scOPC. Exposure of other factors known to modulate OPC migration (e.g. bFGF, Endothelin-1) did not exhibit remarkable differences between cOPCs or scOPC. To identify candidate genes that contribute to the migratory phenotype of scOPCs we performed genes between cOPCs and scOPCs, which are involved in cell migration or polarity. These candidate genes were further verified by q-RT-PCR in neonatal as well as adult OPCs. One of the analyzed genes is Skap2, a scr-kinase associated protein, which is a downstream target of Fyn kinase and was previously identified to play a role in migration and adhesion of other cell types i.e. macrophages. In vitro lentiviral knockdown with Skap2 shRNAs decreased migration of OPCs, but did not influence differentiation into mature oligodendrocytes. Thus, our data indicates the potential involvement of Skap2 in regulation of OPC migration. Spinal cord injury (SCI) results in neural loss and consequently motor and sensory deficit below the injury. Here we have report the regenerative effects and significant improvement of locomotor function in complete transection rat model of SCI following transplantation of oligodendrocyte progenitors cells (OPC) and motoneuron progenitors (MP) derived from hESC. Transplantation of these progenitors promote astrogliosis, thorough activation of jagged1-dependent Notch and Jak/STAT signalling supporting axonal survival. Induction of astrogliosis and neurogenesis can be achieved by inhibition of glycogen synthase kinase-3 (GSK3) well known molecule involved in se...

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RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury

Cited by 395 publications

References 59 publications

Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner

Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner

Current Mechanistic Concepts in Ischemia and Reperfusion Injury

GLIA Edinburgh 2017: Abstracts Oral Presentations, Posters, Indexes

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