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Japanese Encephalitis Virus-induced let-7a/b interacted with the NOTCH-TLR7 pathway in microglia and facilitated neuronal death via caspase activation.

Abstract：

:MicroRNAs (miRNAs) released from the activated microglia upon neurotropic virus infection may exacerbate the neuronal damage. Here, we identified let-7a and let-7b (let-7a/b) as one of the essential miRNAs over-expressed upon Japanese Encephalitis virus (JEV) infection and released in the culture supernatant of the JEV-infected microglial cells through extracellular vesicles. The let-7a/b was previously reported to modulate inflammation in microglial cells through Toll-like receptor 7 (TLR7) pathways; although their role in accelerating JEV pathogenesis remain unexplored. Therefore, we studied the role of let-7a/b in modulating microglia-mediated inflammation during JEV infection and investigated the effect of let-7a/b-containing exosomes on primary neurons. To this end, we examined let-7a/b and NOTCH signaling pathway in TLR7 knockdown (KD) mice. We observed that TLR7 KD or inhibition of let-7a/b suppressed the JEV-induced NOTCH activation possibly via NF-κB dependent manner and subsequently, attenuated JEV-induced TNFα production in microglial cells. Furthermore, exosomes secreted from let-7a/b over-expressed microglia when transferred to uninfected mice brain induced caspase activation. Exosomes secreted from virus-infected or let-7a/b over-expressed microglia when co-incubated with mouse neuronal (Neuro2a) cells or primary cortical neurons also facilitated caspase activation leading to neuronal death. Thus, our results provide evidence for the multifaceted role of let-7a/b miRNAs in JEV pathogenesis. Let-7a/b can interact with TLR7 and NOTCH signaling pathway and enhance TNFα release from microglia. On the other hand, the exosomes secreted by JEV-infected microglia can activate caspases in uninfected neuronal cells which possibly contribute to bystander neuronal death. Cover Image for this issue: doi: 10.1111/jnc.14506.

journal_name

J Neurochem

journal_title

Journal of neurochemistry

authors

Mukherjee S,Akbar I,Kumari B,Vrati S,Basu A,Banerjee A

doi

10.1111/jnc.14645

subject

Has Abstract

pub_date

2019-05-01 00:00:00

pages

518-534

issue

eissn

0022-3042

issn

1471-4159

journal_volume

149

pub_type

杂志文章

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Japanese Encephalitis Virus-induced let-7a/b interacted with the NOTCH-TLR7 pathway in microglia and facilitated neuronal death via caspase activation.