Gas6 attenuates lipopolysaccharide‑induced TNF‑α�expression and apoptosis in H9C2 cells through NF‑κB and�MAPK inhibition via the Axl/PI3K/Akt pathway

Li, Mengfang; Ye, Jingjing; Zhao, Guangju; Hong, Guangliang; Hu, Xiyi; Cao, K Q; Wu, You; Lu, Zhongqiu

doi:10.3892/ijmm.2019.4275

Cited by 42 publications

(35 citation statements)

References 48 publications

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“…Axl has been shown to promote cell survival and inhibit cell apoptosis and pyroptosis by activating PI3K-Akt signaling ( 25 , 26 ), and the RNA-Seq results also indicated that PI3K-Akt signaling was inhibited in Axl −/− macrophages. To confirm this result, we examined the expression of PI3K-p110 and phosphorylated Akt (pAkt) in JEV-infected in situ macrophages using IF staining ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Axl Deficiency Promotes the Neuroinvasion of Japanese Encephalitis Virus by Enhancing IL-1α Production from Pyroptotic Macrophages

Wang

Zhen

Fan

et al. 2020

J Virol

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Japanese encephalitis virus (JEV) is a flavivirus that causes Japanese encephalitis (JE), which has an unclear pathogenesis. Despite vaccination, thousands of deaths attributed to JE are reported annually. In this study, we report that mice deficient for Axl, a receptor tyrosine kinase that plays multiple roles in flaviviral infection, displayed greater mortality upon JEV infection. The effect of Axl deficiency on JEV infection was mediated by markedly elevated serum interleukin-1α (IL-1α) levels, which devastated the blood-brain-barrier and promoted viral neuroinvasion within 24 h post infection. Using an in situ infection model, we showed that dead macrophages were the primary source of observed increased serum IL-1α levels. Axl deficiency enhanced cell death and caused pyroptosis in 80% of JEV-infected macrophages by disrupting PI3K-Akt signaling. Intriguingly, the primary effector released by pyroptotic macrophages in our model was IL-1α rather than IL-1β. Finally, we assessed the effect of an IL-1α antagonist and demonstrated that it effectively prevented the incidence of JE. Our results indicate that Axl plays a protective role in JEV infection, identify IL-1α released by pyroptotic macrophages as a crucial factor promoting JEV neuroinvasion, and suggest that an IL-1α antagonist may be a candidate for JE therapy. IMPORTANCE Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus that causes Japanese encephalitis (JE), the most commonly diagnosed viral encephalitis worldwide. The fatality rate of JE is 20%, and nearly half of the surviving patients develop neuropsychiatric sequelae. Axl is a receptor tyrosine kinase that plays multiple roles in flaviviral infections. Currently, the involvement of Axl in JEV infection remains enigmatic. In this study, we demonstrate that Axl impedes the pathogenesis of severe JE in mice by maintaining blood-brain-barrier (BBB) integrity and restricting viral neuroinvasion. Furthermore, serum IL-1α is a key mediator of this process and is primarily released by JEV-infected pyroptotic macrophages to elicit BBB breakdown, while an IL-1α antagonist can effectively reduce the incidence of severe JE. Our work uncovers the protective role of Axl in antagonizing severe JE and shows that the use of IL-1α antagonist may be a promising tactic to prevent severe JE.

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Section: Resultsmentioning

confidence: 99%

Axl Deficiency Promotes the Neuroinvasion of Japanese Encephalitis Virus by Enhancing IL-1α Production from Pyroptotic Macrophages

Wang

Zhen

Fan

et al. 2020

J Virol

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“…The present study in microglia also concurs with previous reports of the negative regulatory role of Gas6 in inflammatory signaling in other cells. For example, Gas6 has previously been shown to have a suppressive effect on TLR-mediated pro-inflammatory cytokine production in cardiomyocytes (Grommes et al, 2008), microglial cell lines (Li et al, 2019), mouse macrophages (Deng et al, 2011) and primary murine microglia (Binder et al, 2008). There is growing evidence linking alleviation of inflammation to morphological alterations in microglia which are associated with pro-inflammatory signaling responses and cytokine expression (Zhang et al, 2014(Zhang et al, , 2019Kalakh and Mouihate, 2017;Honjoh et al, 2019).…”

Section: Gas6mentioning

confidence: 99%

Gas6 Inhibits Toll-Like Receptor-Mediated Inflammatory Pathways in Mouse Microglia via Axl and Mer

Gilchrist

Goudarzi

Hafizi

2020

Front. Cell. Neurosci.

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Background: Microglia are well known key regulators of neuroinflammation which feature in multiple neurodegenerative disorders. These cells survey the CNS and, under inflammatory conditions, become "activated" through stimulation of toll-like receptors (TLRs), resulting in changes in morphology and production and release of cytokines. In the present study, we examined the roles of the related TAM receptors, Mer and Axl, and of their ligand, Gas6, in the regulation of microglial pro-inflammatory TNF-α production and microglial morphology. Methods: Primary cultures of murine microglia of wild-type (WT), Mer −/− and Axl −/− backgrounds were stimulated by the TLR4 agonist, lipopolysaccharide (LPS) with or without pre-treatment with Gas6. Gene expression of TNF-α, Mer, and Axl was examined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA) was used to measure TNF-α release from microglia. Immunofluorescence staining of β-actin and the microglial marker Iba1 was performed to reveal microglial morphological changes, with cellular characteristics (area, perimeter, Feret's diameter, minimum Feret, roundness, and aspect ratio) being quantified using ImageJ software. Results: Under basal conditions, TNF-α gene expression was significantly lower in Axl −/− microglia compared to WT cells. However, all microglial cultures robustly responded to LPS stimulation with the upregulation of TNF-α expression to similar degrees. Furthermore, Mer receptor expression was less responsive to LPS stimulation when in Axl knockout cells. The presence of Gas6 consistently inhibited the LPS-induced upregulation of TNF-α in WT, Mer −/− and Axl −/− microglia. Moreover, Gas6 also inhibited LPS-induced changes in the microglial area, perimeter length, and cell roundness in wild-type cells.

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“…Gas6 regulates several biological functions, such as cell growth, myelination, and mitogenesis, via the activation of the receptor tyrosine kinases of the Tyros3, Axl, and Mer (TAM) family [ 40 , 46 ]. In the nervous system, Gas6 has been shown to prevent cell apoptosis through activation of the PI3K associated protein kinase B (Akt) and Bcl-2-associated death promoter protein (Bad) (PI3K/Akt/Bad)-signaling pathway [ 47 , 48 ]. In Alzheimer’s disease patients, the protein level of Gas6 in the cerebrospinal fluid was found to be elevated [ 49 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanism of Vitamin K2 Protection against Amyloid-β-Induced Cytotoxicity

2021

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The pathological role of vitamin K2 in Alzheimer’s disease (AD) involves a definite link between impaired cognitive functions and decreased serum vitamin K levels. Vitamin K2 supplementation may have a protective effect on AD. However, the mechanism underlying vitamin K2 protection has not been elucidated. With the amyloid-β (Aβ) cascade hypothesis, we constructed a clone containing the C-terminal fragment of amyloid precursor protein (β-CTF/APP), transfected in astroglioma C6 cells and used this cell model (β-CTF/C6) to study the protective effect of vitamin K2 against Aβ cytotoxicity. Both cellular and biochemical assays, including cell viability and reactive oxygen species (ROS), assays assay, and Western blot and caspase activity analyses, were used to characterize and unveil the protective role and mechanism of vitamin K2 protecting against Aβ-induced cytotoxicity. Vitamin K2 treatment dose-dependently decreased the death of neural cells. The protective effect of vitamin K2 could be abolished by adding warfarin, a vitamin K2 antagonist. The addition of vitamin K2 reduced the ROS formation and inhibited the caspase-3 mediated apoptosis induced by Aβ peptides, indicating that the mechanism underlying the vitamin K2 protection is likely against Aβ-mediated apoptosis. Inhibitor assay and Western blot analyses revealed that the possible mechanism of vitamin K2 protection against Aβ-mediated apoptosis might be via regulating phosphatidylinositol 3-kinase (PI3K) associated-signaling pathway and inhibiting caspase-3-mediated apoptosis. Our study demonstrates that vitamin K2 can protect neural cells against Aβ toxicity.

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Gas6 attenuates lipopolysaccharide‑induced TNF‑α�expression and apoptosis in H9C2 cells through NF‑κB and�MAPK inhibition via the Axl/PI3K/Akt pathway

Cited by 42 publications

References 48 publications

Axl Deficiency Promotes the Neuroinvasion of Japanese Encephalitis Virus by Enhancing IL-1α Production from Pyroptotic Macrophages

Axl Deficiency Promotes the Neuroinvasion of Japanese Encephalitis Virus by Enhancing IL-1α Production from Pyroptotic Macrophages

Gas6 Inhibits Toll-Like Receptor-Mediated Inflammatory Pathways in Mouse Microglia via Axl and Mer

Molecular Mechanism of Vitamin K2 Protection against Amyloid-β-Induced Cytotoxicity

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