Japanese Encephalitis Virus infection induces IL-18 and IL-1β in microglia and astrocytes: Correlation with in vitro cytokine responsiveness of glial cells and subsequent neuronal death

Das, Sulagna; Mishra, Manoj Kumar; Ghosh, Joydeep; Basu, Anirban

doi:10.1016/j.jneuroim.2008.01.009

Cited by 95 publications

(87 citation statements)

References 35 publications

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“…The causative effect of activated microglia in JEV-associated neuronal damage was demonstrated further by in vitro cell line studies. JEV infection-stimulated and cytokine-activated microglial cell lines produced neurotoxic mediators that caused neuronal death in neuronal cell lines (Ghoshal et al, 2007;Das et al, 2008;Swarup et al, 2008). In parallel with these findings, the present study elicited the inductive characteristics of glia by JEV infection and showed the neurotoxic potential of activated microglia via primary culture models.…”

Section: Discussionsupporting

confidence: 83%

“…TNF-a and IL-1b are potentially neurotoxic molecules in JEVassociated neuronal death, as both neutralizing antibodies attenuated JEV-induced neuronal death (Fig. 8) and both TNF-a and IL-1b have been shown to directly and indirectly injure neurons (Raung et al, 2005(Raung et al, , 2007Ghoshal et al, 2007;Swarup et al, 2007Swarup et al, , 2008Das et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, many studies have demonstrated that astrocytes and microglia showed distinct alterations in response to JEV infection. JEV infection caused the release of TNF-a, IL-1b, IL-6, IL-18 and monocyte chemotatic protein-1 (MCP-1) in microglial cell lines and expression of inducible nitric oxide synthase and cyclooxygenase-2 (Ghoshal et al, 2007;Das et al, 2008). JEV-infected astrocyte cell lines have been shown to express IL-1b, IL-6, IL-8, IL-18, MCP-1 and IP-10 (Das et al, 2008;.…”

Section: Discussionmentioning

confidence: 99%

“…It has been demonstrated that the mortality rate increases with increasing concentrations of cytokines in the serum and CSF in Japanese encephalitis patients (Ravi et al, 1997). Regarding JEV-associated neuroinflammation, a number of studies have shown that JEV infects microglia and astrocytes, and their consequent activation contributes to neuronal death (Chen et al, 2000(Chen et al, , 2004Raung et al, 2005Raung et al, , 2007Abraham & Manjunath, 2006;Bhowmick et al, 2007;Ghoshal et al, 2007;Mishra et al, 2007;Das et al, 2008;Swarup et al, 2008). These studies suggest that, in addition to direct viral infection of neurons, bystander damage caused by activated microglia/ astrocytes is involved in JEV-induced neuronal death.…”

Section: Introductionmentioning

confidence: 99%

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Glial activation involvement in neuronal death by Japanese encephalitis virus infection

Chen

Lin

et al. 2009

Journal of General Virology

146

153

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Japanese encephalitis is characterized by profound neuronal destruction/dysfunction and concomitant microgliosis/astrogliosis. Although substantial activation of glia is observed in Japanese encephalitis virus (JEV)-induced Japanese encephalitis, the inflammatory responses and consequences of astrocytes and microglial activation after JEV infection are not fully understood. In this study, infection of cultured neurons/glia with JEV caused neuronal death and glial activation, as evidenced by morphological transformation, increased cell proliferation and elevated tumour necrosis factor (TNF)-a, interleukin (IL)-1b, IL-6 and RANTES (regulated upon activation, normal T-cell expressed and secreted) production. Replication-competent JEV caused all glial responses and neurotoxicity. However, replication-incompetent JEV lost these abilities, except for the ability to change microglial morphology. The bystander damage caused by activated glia also contributed to JEV-associated neurotoxicity. Microglia underwent morphological changes, increased cell proliferation and elevated TNF-a, IL-1b, IL-6 and RANTES expression in response to JEV infection. In contrast, IL-6 and RANTES expression, but no apparent morphological changes, proliferation or TNF-a/IL-1b expression, was demonstrated in JEV-infected astrocytes. Supernatants of JEV-infected microglia, but not JEV-infected astrocytes, induced glial activation and triggered neuronal death. Antibody neutralization studies revealed that TNF-a and IL-1b, but not RANTES or IL-6, released by activated microglia appeared to play roles in JEV-associated neurotoxicity. In conclusion, following JEV infection, neuronal death was accompanied by concomitant microgliosis and astrogliosis, and neurotoxic mediators released by JEV-activated microglia, rather than by JEV-activated astrocytes, had the ability to amplify the microglial response and cause neuronal death.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Glial activation involvement in neuronal death by Japanese encephalitis virus infection

Chen

Lin

et al. 2009

Journal of General Virology

146

153

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“…Effects of miR-15b on JEV-triggered inflammatory cytokine production JEV-associated encephalitis is characterized by activation of resident glial cells and excessive production of inflammatory cytokines, which contributes to neuronal death (6,45). To investigate whether miR-15b could affect the JEV-triggered inflammatory response, its effect on the regulation of inflammatory cytokine production after JEV challenge was assessed.…”

Section: Upregulation Of Mir-15b Upon Jev Infectionmentioning

confidence: 99%

MicroRNA-15b Modulates Japanese Encephalitis Virus–Mediated Inflammation via Targeting RNF125

Zhu

Nie

et al. 2015

The Journal of Immunology

100

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Japanese encephalitis virus (JEV) can target CNS and cause neuroinflammation that is characterized by profound neuronal damage and concomitant microgliosis/astrogliosis. Although microRNAs (miRNAs) have emerged as a major regulatory network with profound effects on inflammatory response, it is less clear how they regulate JEV-induced inflammation. In this study, we found that miR-15b is involved in modulating the JEV-induced inflammatory response. The data demonstrate that miR-15b is upregulated during JEV infection of glial cells and mouse brains. In vitro overexpression of miR-15b enhances the JEV-induced inflammatory response, whereas inhibition of miR-15b decreases it. Mechanistically, ring finger protein 125 (RNF125), a negative regulator of RIG-I signaling, is identified as a direct target of miR-15b in the context of JEV infection. Furthermore, inhibition of RNF125 by miR-15b results in an elevation in RIG-I levels, which, in turn, leads to a higher production of proinflammatory cytokines and type I IFN. In vivo knockdown of virus-induced miR-15b by antagomir-15b restores the expression of RNF125, reduces the production of inflammatory cytokines, attenuates glial activation and neuronal damage, decreases viral burden in the brain, and improves survival in the mouse model. Taken together, our results indicate that miR-15b modulates the inflammatory response during JEV infection by negative regulation of RNF125 expression. Therefore, miR-15b targeting may constitute an interesting and promising approach to control viral-induced neuroinflammation.

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Cerebrospinal Fluid Cytokines Correlate With Aseptic Meningitis and Blood–Brain Barrier Function in Neonatal‐Onset Multisystem Inflammatory Disease: Central Nervous System Biomarkers in Neonatal‐Onset Multisystem Inflammatory Disease Correlate With Central Nervous System Inflammation

Rodriguez-Smith

Lin

Tsai

et al. 2017

Arthritis & Rheumatology

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Objective To evaluate proinflammatory cytokines and leukocyte subpopulations in cerebrospinal spinal fluid (CSF) and blood of NOMID patients post-treatment; and to compare inflammatory cytokines in CSF and blood in 6 patients treated with two IL-1 blockers, anakinra and canakinumab. Methods We immunophenotyped CSF on 17 anakinra-treated pediatric NOMID patients during routine follow-up visits between December 2011 and October 2013 and analyzed CSF cytokine levels in baseline and 3–5 years follow-up samples compared to healthy controls. Results Elevated CSF IL-6, IP-10/CXCL10, IL-18 levels, and monocyte and granulocytes counts significantly decreased with anakinra treatment, but did not normalize to control levels, even in patients fulfilling criteria of “clinical remission” (CR). CSF IL-6 and IL-18 levels significantly correlate with measures of blood brain barrier (BBB) function, specifically CSF protein (r=0.75; r=0.81 respectively); and albumin quotient (r=0.79, r=0.68 respectively). Median CSF WBC levels (10.2 vs. 3.7cell/mm3) and CSF IL-6 levels (150.7 vs. 28.5pg/ml) were significantly higher when patients received canakinumab than anakinra despite similar serum cytokine levels. Conclusions CSF leukocyte subpopulations and cytokine levels significantly improve with optimized IL-1 blocking treatment but do not normalize. The correlation of CSF IL-6, IP-10/CXCL10 and IL-18 with clinical-laboratory measures of inflammation and BBB function suggests a role as biomarkers in CNS inflammation. The difference in inhibition of CSF biomarkers between two IL-1 blocking agents, anakinra and canakinumab, suggests differences in efficacy in the intrathecal compartment, with anakinra being more effective. Our data indicate that intrathecal immune responses shape CNS inflammation and should be assessed in addition to blood markers. Clinical trial identifier (NCT00059748 and NCT00069329)

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Japanese Encephalitis Virus infection induces IL-18 and IL-1β in microglia and astrocytes: Correlation with in vitro cytokine responsiveness of glial cells and subsequent neuronal death

Cited by 95 publications

References 35 publications

Glial activation involvement in neuronal death by Japanese encephalitis virus infection

Glial activation involvement in neuronal death by Japanese encephalitis virus infection

MicroRNA-15b Modulates Japanese Encephalitis Virus–Mediated Inflammation via Targeting RNF125

Cerebrospinal Fluid Cytokines Correlate With Aseptic Meningitis and Blood–Brain Barrier Function in Neonatal‐Onset Multisystem Inflammatory Disease: Central Nervous System Biomarkers in Neonatal‐Onset Multisystem Inflammatory Disease Correlate With Central Nervous System Inflammation

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