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miR-301a Regulates Inflammatory Response to Japanese Encephalitis Virus Infection via Suppression of NKRF Activity

Bibhabasu Hazra, Surajit Chakraborty, Meenakshi Bhaskar, Sriparna Mukherjee, Anita Mahadevan and Anirban Basu
J Immunol September 16, 2019, ji1900003; DOI: https://doi.org/10.4049/jimmunol.1900003
Bibhabasu Hazra
*National Brain Research Centre, Manesar, Haryana 122052, India; and
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Surajit Chakraborty
*National Brain Research Centre, Manesar, Haryana 122052, India; and
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Meenakshi Bhaskar
*National Brain Research Centre, Manesar, Haryana 122052, India; and
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Sriparna Mukherjee
*National Brain Research Centre, Manesar, Haryana 122052, India; and
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Anita Mahadevan
†Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore 560029, India
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Anirban Basu
*National Brain Research Centre, Manesar, Haryana 122052, India; and
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Key Points

  • JEV infection elicits miR-301a upregulation in microglial cells.

  • miR-301a upregulation reduces NKRF abundance, thus amplifying NF-κB signaling.

  • Inhibiting miR-301a reduces microglia-mediated bystander killing of neurons.

Abstract

Microglia being the resident macrophage of brain provides neuroprotection following diverse microbial infections. Japanese encephalitis virus (JEV) invades the CNS, resulting in neuroinflammation, which turns the neuroprotective role of microglia detrimental as characterized by increased microglial activation and neuronal death. Several host factors, including microRNAs, play vital roles in regulating virus-induced inflammation. In the current study, we demonstrate that the expression of miR-301a is increased in JEV-infected microglial cells and human brain. Overexpression of miR-301a augments the JEV-induced inflammatory response, whereas inhibition of miR-301a completely reverses the effects. Mechanistically, NF-κB–repressing factor (NKRF) functioning as inhibitor of NF-κB activation is identified as a potential target of miR-301a in JEV infection. Consequently, miR-301a–mediated inhibition of NKRF enhances nuclear translocation of NF-κB, which, in turn, resulted in amplified inflammatory response. Conversely, NKRF overexpression in miR-301a–inhibited condition restores nuclear accumulation of NF-κB to a basal level. We also observed that JEV infection induces classical activation (M1) of microglia that drives the production of proinflammatory cytokines while suppressing alternative activation (M2) that could serve to dampen the inflammatory response. Furthermore, in vivo neutralization of miR-301a in mouse brain restores NKRF expression, thereby reducing inflammatory response, microglial activation, and neuronal apoptosis. Thus, our study suggests that the JEV-induced expression of miR-301a positively regulates inflammatory response by suppressing NKRF production, which might be targeted to manage viral-induced neuroinflammation.

Footnotes

  • This work was supported by research grants from the Department of Biotechnology (BT/PR22341/MED/122/55/2016) and the Tata Innovation Fellowship (BT/HRD/35/01/02/2014) to A.B.

  • The online version of this article contains supplemental material.

  • Received January 3, 2019.
  • Accepted August 20, 2019.
  • Copyright © 2019 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 206 (2)
The Journal of Immunology
Vol. 206, Issue 2
15 Jan 2021
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miR-301a Regulates Inflammatory Response to Japanese Encephalitis Virus Infection via Suppression of NKRF Activity
Bibhabasu Hazra, Surajit Chakraborty, Meenakshi Bhaskar, Sriparna Mukherjee, Anita Mahadevan, Anirban Basu
The Journal of Immunology September 16, 2019, ji1900003; DOI: 10.4049/jimmunol.1900003

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miR-301a Regulates Inflammatory Response to Japanese Encephalitis Virus Infection via Suppression of NKRF Activity
Bibhabasu Hazra, Surajit Chakraborty, Meenakshi Bhaskar, Sriparna Mukherjee, Anita Mahadevan, Anirban Basu
The Journal of Immunology September 16, 2019, ji1900003; DOI: 10.4049/jimmunol.1900003
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