Mukherjee, Sriparna and Akbar, Irshad and Kumari, Bharti and Vrati, Sudhanshu and Basu, Anirban and Banerjee, Arup (2019) Japanese Encephalitis Virus‐induced let‐7a/b interacted with the NOTCH ‐ TLR 7 pathway in microglia and facilitated neuronal death via caspase activation. Journal of Neurochemistry, 149 (4). pp. 518-534. ISSN 0022-3042

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Abstract

*National Brain Research Center, Manesar, India†Translational Health Science and Technology Institute, Faridabad, India‡Regional Center for Biotechnology, Faridabad, IndiaAbstractMicroRNAs (miRNAs) released from the activated microgliaupon neurotropic virus infection may exacerbate the neuronaldamage. Here, we identified let-7a and let-7b (let-7a/b) as oneof the essential miRNAs over-expressed upon JapaneseEncephalitis virus (JEV) infection and released in the culturesupernatant of the JEV-infected microglial cells throughextracellular vesicles. The let-7a/b was previously reportedto modulate inflammation in microglial cells through Toll-likereceptor 7 (TLR7) pathways; although their role in acceleratingJEV pathogenesis remain unexplored. Therefore, we studiedthe role of let-7a/b in modulating microglia-mediated inflam-mation 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 TLR7knockdown (KD) mice. We observed that TLR7 KD orinhibition of let-7a/b suppressed the JEV-induced NOTCHactivation possibly via NF-jB dependent manner and subse-quently, attenuated JEV-induced TNFa production in micro-glial cells. Furthermore, exosomes secreted from let-7a/bover-expressed microglia when transferred to uninfected micebrain induced caspase activation. Exosomes secreted fromvirus-infected or let-7a/b over-expressed microglia when co-incubated with mouse neuronal (Neuro2a) cells or primarycortical neurons also facilitated caspase activation leading toneuronal death. Thus, our results provide evidence for themultifaceted role of let-7a/b miRNAs in JEV pathogenesis. Let-7a/b can interact with TLR7 and NOTCH signaling pathwayand enhance TNFa release from microglia. On the other hand,the exosomes secreted by JEV-infected microglia can activatecaspases in uninfected neuronal cells which possibly con-tribute to bystander neuronal death.

Item Type:	Article
Subjects:	Biomedical Science
Depositing User:	RCB Library
Date Deposited:	25 Jun 2020 07:01
Last Modified:	25 Jun 2020 07:01
URI:	http://rcb.sciencecentral.in/id/eprint/277

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