MLKL Mediated Necroptosis Accelerates JEV-Induced Neuroinflammation in Mice

Bian, Peiyu; Zheng, Xiaoliang; Li, Wei; Ye, Chuantao; Fan, Hong; Cai, Yanhui; Zhang, Ying; Zhang, Fanglin; Jia, Zhansheng; Lei, Yingfeng

doi:10.3389/fmicb.2017.00303

Cited by 34 publications

(27 citation statements)

References 37 publications

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“…Unlike apoptosis, pyroptosis is accompanied by the release of IL-1β, IL-18, and other pro-inflammatory cytokines, causing vehement inflammatory responses. Currently, necroptotic death induced by JEV infection has only been reported in neurons [25]. Our results suggest that a number of JEV-infected macrophages underwent necroptosis.…”

Section: Discussionmentioning

confidence: 47%

Transcriptomic Analysis Suggests the M1 Polarization and Launch of Diverse Programmed Cell Death Pathways in Japanese Encephalitis Virus-Infected Macrophages

Wang

Zhen

Fan

et al. 2020

Viruses

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The Japanese encephalitis virus (JEV) is a Culex mosquito-borne flavivirus and is the pathogenic agent of Japanese encephalitis, which is the most important type of viral encephalitis in the world. Macrophages are a type of pivotal innate immunocyte that serve as sentinels and respond quickly to pathogen invasions. However, some viruses like JEV can hijack macrophages as a refuge for viral replication and immune escape. Despite their crucial involvement in early JEV infection, the transcriptomic landscapes of JEV-infected macrophages are void. Here, by using an in situ JEV infection model, we investigate the transcriptomic alteration of JEV-infected peritoneal macrophages. We found that, upon JEV infection, the macrophages underwent M1 polarization and showed the drastic activation of innate immune and inflammatory pathways. Interestingly, almost all the programmed cell death (PCD) pathways were activated, especially the apoptosis, pyroptosis, and necroptosis pathways, which were verified by the immunofluorescent staining of specific markers. Further transcriptomic analysis and TUNEL staining revealed that JEV infection caused apparent DNA damage. The transcriptomic analysis also revealed that JEV infection promoted ROS and RNS generation and caused oxidative stress, which activated multiple cell death pathways. Our work uncovers the pivotal pathogenic roles of oxidative stress and multiple PCD pathways in JEV infection, providing a novel perspective on JEV–host interactions.

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Section: Discussionmentioning

confidence: 47%

Transcriptomic Analysis Suggests the M1 Polarization and Launch of Diverse Programmed Cell Death Pathways in Japanese Encephalitis Virus-Infected Macrophages

Wang

Zhen

Fan

et al. 2020

Viruses

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“…Necroptosis participates in nervous-system pathologies with prominent axonal degeneration, such as multiple sclerosis (Ofengeim et al, 2015), ALS Ito et al, 2016), PD (Iannielli et al, 2018), AD (Caccamo et al, 2017), and neuroinflammation (Bian et al, 2017;Daniels et al, 2017), among others Vieira et al, 2014). This research has established that there are both neuronal-autonomous roles for necroptosis and noncell autonomous mechanisms participating in nervous-system dysfunction (Tonnus and Linkermann, 2017).…”

Section: Introductionmentioning

confidence: 99%

Axonal Degeneration Is Mediated by Necroptosis Activation

et al. 2019

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Axonal degeneration, which contributes to functional impairment in several disorders of the nervous system, is an important target for neuroprotection. Several individual factors and subcellular events have been implicated in axonal degeneration, but researchers have so far been unable to identify an integrative signaling pathway activating this self-destructive process. Through pharmacological and genetic approaches, we tested whether necroptosis, a regulated cell-death mechanism implicated in the pathogenesis of several neurodegenerative diseases, is involved in axonal degeneration. Pharmacological inhibition of the necroptotic kinase RIPK1 using necrostatin-1 strongly delayed axonal degeneration in the peripheral nervous system and CNS of wild-type mice of either sex and protected in vitro sensory axons from degeneration after mechanical and toxic insults. These effects were also observed after genetic knock-down of RIPK3, a second key regulator of necroptosis, and the downstream effector MLKL (Mixed Lineage Kinase Domain-Like). RIPK1 inhibition prevented mitochondrial fragmentation in vitro and in vivo, a typical feature of necrotic death, and inhibition of mitochondrial fission by Mdivi also resulted in reduced axonal loss in damaged nerves. Furthermore, electrophysiological analysis demonstrated that inhibition of necroptosis delays not only the morphological degeneration of axons, but also the loss of their electrophysiological function after nerve injury. Activation of the necroptotic pathway early during injury-induced axonal degeneration was made evident by increased phosphorylation of the downstream effector MLKL. Our results demonstrate that axonal degeneration proceeds by necroptosis, thus defining a novel mechanistic framework in the axonal degenerative cascade for therapeutic interventions in a wide variety of conditions that lead to neuronal loss and functional impairment.

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“…Recent reports associated the activation of necroptosis to several neurodegenerative conditions (reviewed in Yuan et al, 2019). Inhibition of necroptosis with small molecules or genetic ablation of RIPK1, RIPK3 or MLKL exert neuroprotective effects in models of brain damage, including ischemia (Qu et al, 2016;Yin et al, 2015;Zhang et al, 2016b), traumatic injury (You et al, 2008), viral infections (Bian et al, 2017), in addition to contribute to retinal damage (Dong et al, 2012;Kim et al, 2016;Viringipurampeer et al, 2014) and spinal cord injury (Liu et al, 2015). Recent advances in the field have demonstrated the therapeutic potential of inhibiting necroptosis in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) (Ito et al, 2016;Re et al, 2014) multiple sclerosis (MS) (Ofengeim et al, 2015) and Alzheimer's disease (AD) (Caccamo et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

The necroptosis machinery mediates axonal degeneration in a model of Parkinson disease

Oñate

Catenaccio

Salvadores

et al. 2019

Preprint

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Parkinson's disease (PD) is the second most common neurodegenerative condition, characterized by motor impairment due to the progressive degeneration of dopaminergic neurons in the substantia nigra and depletion of dopamine release in the striatum.Accumulating evidence suggest that degeneration of axons is an early event in the disease, involving destruction programs that are independent of the survival of the cell soma. Necroptosis, a programmed cell death process, is emerging as a mediator of neuronal loss in models of neurodegenerative diseases. Here, we demonstrate activation of necroptosis in postmortem brain tissue from PD patients and in a toxin-based mouse model of the disease. Inhibition of key components of the necroptotic pathway resulted in a significant delay of 6-hydroxydopamine dependent axonal degeneration of dopaminergic and cortical neurons in vitro. Genetic ablation of necroptosis mediators MLKL and RIPK3, as well as pharmacological inhibition of RIPK1 in vivo, decreased dopaminergic neuron degeneration, improving motor performance. Together, these findings suggest that axonal degeneration in PD is mediated by the necroptosis machinery, a process here referred to as necroaxoptosis, a druggable pathway to target dopaminergic neuronal loss.

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MLKL Mediated Necroptosis Accelerates JEV-Induced Neuroinflammation in Mice

Cited by 34 publications

References 37 publications

Transcriptomic Analysis Suggests the M1 Polarization and Launch of Diverse Programmed Cell Death Pathways in Japanese Encephalitis Virus-Infected Macrophages

Transcriptomic Analysis Suggests the M1 Polarization and Launch of Diverse Programmed Cell Death Pathways in Japanese Encephalitis Virus-Infected Macrophages

Axonal Degeneration Is Mediated by Necroptosis Activation

The necroptosis machinery mediates axonal degeneration in a model of Parkinson disease

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