The E3 Ubiquitin Ligase c‐Cbl Inhibits Microglia‐Mediated <scp>CNS</scp> Inflammation by Regulating <scp>PI</scp>3K/Akt/<scp>NF</scp>‐<i>κ</i>B Pathway

Dong, Lin; Li, Yuzhen; An, Haiting; Wang, Yalong; Chen, Shihao; Qian, Yafang; Wang, Ke; Zhen, Junli; Fan, Zheng; Gong, Xia; Zheng, Yi; Wang, Xiaomin

doi:10.1111/cns.12557

Cited by 36 publications

(24 citation statements)

References 34 publications

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“…RIPK1 inhibitors are being investigated in human clinical trials for neurodegenerative diseases as well, such as ALS and AD, although the precise mechanisms by which RIPK1 kinase activity may contribute to different neurodegenerative conditions remains to be clarified (27,29,30). We show that neuronal, astrocytic, and microglial cultures can undergo RDA in response to TNFα and identify four RDA regulators, c-Cbl, Apc11, Lrrk2, and Nek1, which are highly expressed in the CNS (48,49). Astrocytes in particular express all four genes at high levels, and, interestingly, microglia, which are most sensitive to RDA, are reported to have low expression of RDA suppressor Nek1 (49).…”

Section: Discussionmentioning

confidence: 93%

Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFα-mediated apoptosis

Amin

Florez

Najafov

et al. 2018

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

116

112

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Stimulation of cells with TNFα can promote distinct cell death pathways, including RIPK1-independent apoptosis, necroptosis, and RIPK1-dependent apoptosis (RDA)-the latter of which we still know little about. Here we show that RDA involves the rapid formation of a distinct detergent-insoluble, highly ubiquitinated, and activated RIPK1 pool, termed "iuRIPK1." iuRIPK1 forms after RIPK1 activation in TNF-receptor-associated complex I, and before cytosolic complex II formation and caspase activation. To identify regulators of iuRIPK1 formation and RIPK1 activation in RDA, we conducted a targeted siRNA screen of 1,288 genes. We found that NEK1, whose loss-of-function mutations have been identified in 3% of ALS patients, binds to activated RIPK1 and restricts RDA by negatively regulating formation of iuRIPK1, while LRRK2, a kinase implicated in Parkinson's disease, promotes RIPK1 activation and association with complex I in RDA. Further, the E3 ligases APC11 and c-Cbl promote RDA, and c-Cbl is recruited to complex I in RDA, where it promotes prodeath K63-ubiquitination of RIPK1 to lead to iuRIPK1 formation. Finally, we show that two different modes of necroptosis induction by TNFα exist which are differentially regulated by iuRIPK1 formation. Overall, this work reveals a distinct mechanism of RIPK1 activation that mediates the signaling mechanism of RDA as well as a type of necroptosis.

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Section: Discussionmentioning

confidence: 93%

Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFα-mediated apoptosis

Amin

Florez

Najafov

et al. 2018

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

116

112

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“…The NF-κB signaling pathway is involved in regulating inflammation and BBB integrity in cerebral ischemia and neurodegenerative diseases [ 19 , 33 , 34 ]. The PI3K/Akt signaling is well known as a major upstream element of the NF-κB signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…The activation of PI3K/Akt/NF-κB pathway is involved in the stabilization of BBB integrity by increasing the expression of tight junction proteins and the alleviation of inflammation via decreasing inflammatory mediators in stroke and neurodegenerative disease [ 17 – 19 ]. Recent studies showed that Aggf1 possessed the protective roles by activating PI3K/Akt pathway in myocardial ischemia-reperfusion injury and in cell cultures [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Aggf1 attenuates neuroinflammation and BBB disruption via PI3K/Akt/NF-κB pathway after subarachnoid hemorrhage in rats

Zhu

Enkhjargal

Huang

et al. 2018

J Neuroinflammation

118

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BackgroundNeuroinflammation and blood-brain barrier (BBB) disruption are two critical mechanisms of subarachnoid hemorrhage (SAH)-induced brain injury, which are closely related to patient prognosis. Recently, angiogenic factor with G-patch and FHA domain 1 (Aggf1) was shown to inhibit inflammatory effect and preserve vascular integrity in non-nervous system diseases. This study aimed to determine whether Aggf1 could attenuate neuroinflammation and preserve BBB integrity after experimental SAH, as well as the underlying mechanisms of its protective roles.MethodsTwo hundred forty-nine male Sprague-Dawley rats were subjected to the endovascular perforation model of SAH. Recombinant human Aggf1 (rh-Aggf1) was administered intravenously via tail vein injection at 1 h after SAH induction. To investigate the underlying neuroprotection mechanism, Aggf1 small interfering RNA (Aggf1 siRNA) and PI3K-specific inhibitor LY294002 were administered through intracerebroventricular (i.c.v.) before SAH induction. SAH grade, neurological score, brain water content, BBB permeability, Western blot, and immunohistochemistry were performed.ResultsExpression of endogenous Aggf1 was markedly increased after SAH. Aggf1 was primarily expressed in endothelial cells and astrocytes, as well as microglia after SAH. Administration of rh-Aggf1 significantly reduced brain water content and BBB permeability, decreased the numbers of infiltrating neutrophils, and activated microglia in the ipsilateral cerebral cortex following SAH. Furthermore, rh-Aggf1 treatment improved both short- and long-term neurological functions after SAH. Meanwhile, exogenous rh-Aggf1 significantly increased the expression of PI3K, p-Akt, VE-cadherin, Occludin, and Claudin-5, as well as decreased the expression of p-NF-κB p65, albumin, myeloperoxidase (MPO), TNF-α, and IL-1β. Conversely, knockdown of endogenous Aggf1 aggravated BBB breakdown, inflammatory response and neurological impairments at 24 h after SAH. Additionally, the protective roles of rh-Aggf1 were abolished by LY294002.ConclusionsTaken together, exogenous Aggf1 treatment attenuated neuroinflammation and BBB disruption, improved neurological deficits after SAH in rats, at least in part through the PI3K/Akt/NF-κB pathway.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1211-8) contains supplementary material, which is available to authorized users.

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“…PD in most patients is sporadic, as less than 10% of the patients have a family history. The most important pathological change in PD is the degeneration and death of dopaminergic neurons in the substantia nigra of the midbrain, which leads to the significant decrease in dopamine (DA) content in the striatum 78,79 . Excessive microglial phagocytosis of dopaminergic neurons in the substantia nigra may be an important pathogenic mechanism in the pathological process of PD.…”

Section: Nervous System Disease Related To Pathological Microglial Phmentioning

confidence: 99%

Central nervous system diseases related to pathological microglial phagocytosis

et al. 2021

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Microglia are important phagocytes of the central nervous system (CNS). They play an important role in protecting the CNS by clearing necrotic tissue and apoptotic cells in many CNS diseases. However, recent studies have found that microglia can phagocytose parts of neurons excessively, such as the neuronal cell body, synapse, or myelin sheaths, before or after the onset of CNS diseases, leading to aggravated injury and impaired tissue repair. Meanwhile, reduced phagocytosis of synapses and myelin results in abnormal circuit connections and inhibition of remyelination, respectively. Previous studies focused primarily on the positive effects of microglia phagocytosis, whereas only a few studies have focused on the negative effects. In this review, we use the term "pathological microglial phagocytosis" to refer to excessive or reduced phagocytosis by microglia that leads to structural or functional abnormalities in target cells and brain tissue. The classification of pathological microglial phagocytosis, the composition, and activation of related signaling pathways, as well as the process of pathological phagocytosis in various kinds of CNS diseases, are described in this review. We hypothesize that pathological microglial phagocytosis leads to aggravation of tissue damage and negative functional outcome. For example, excessive microglial phagocytosis of synapses can be observed in Alzheimer's disease and schizophrenia, leading to significant synapse loss and memory impairment. In Parkinson's disease, ischemic stroke, and traumatic brain injury, excessive microglial phagocytosis of neuronal cell bodies causes impaired gray matter recovery and sensory dysfunction. We therefore believe that more studies should focus on the mechanism of pathological microglial phagocytosis and activation to uncover potential targets of therapeutic intervention.

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The E3 Ubiquitin Ligase c‐Cbl Inhibits Microglia‐Mediated CNS Inflammation by Regulating PI3K/Akt/NF‐κB Pathway

Abstract: In sum, c-Cbl inhibits expression of LPS-stimulated proinflammatory cytokines and chemokines in microglia. We demonstrate an unprecedented role for c-Cbl in microglia-mediated neuroinflammation involving PI3K/Akt/NF-κB pathway.

Cited by 36 publications

References 34 publications

Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFα-mediated apoptosis

Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFα-mediated apoptosis

Aggf1 attenuates neuroinflammation and BBB disruption via PI3K/Akt/NF-κB pathway after subarachnoid hemorrhage in rats

Central nervous system diseases related to pathological microglial phagocytosis

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