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Mir-301A Regulates Inflammatory Response to Japanese Encephalitis Virus Infection Via Suppression of NKRF Activity

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Mir-301A Regulates Inflammatory Response to Japanese Encephalitis Virus Infection Via Suppression of NKRF Activity miR-301a Regulates Inflammatory Response to Japanese Encephalitis Virus Infection via Suppression of NKRF Activity This information is current as Bibhabasu Hazra, Surajit Chakraborty, Meenakshi Bhaskar, of September 25, 2021. Sriparna Mukherjee, Anita Mahadevan and Anirban Basu J Immunol published online 16 September 2019 http://www.jimmunol.org/content/early/2019/09/13/jimmun ol.1900003 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2019/09/13/jimmunol.190000 Material 3.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 25, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published September 16, 2019, doi:10.4049/jimmunol.1900003 The Journal of Immunology 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* Microglia being the resident macrophage of brain provides neuroprotection following diverse microbial infections. Japanese en- cephalitis virus (JEV) invades the CNS, resulting in neuroinflammation, which turns the neuroprotective role of microglia detri- mental 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 in- creased in JEV-infected microglial cells and human brain. Overexpression of miR-301a augments the JEV-induced inflammatory Downloaded from response, whereas inhibition of miR-301a completely reverses the effects. Mechanistically, NF-kB–repressing factor (NKRF) functioning as inhibitor of NF-kB 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-kB, which, in turn, resulted in amplified inflam- matory response. Conversely, NKRF overexpression in miR-301a–inhibited condition restores nuclear accumulation of NF-kBtoa 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. http://www.jimmunol.org/ 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. The Journal of Immunology, 2019, 203: 000–000. nflammatory response triggered by the activation of innate (2, 3). However, neuronal death as a result of excessive microglial arm of the immune system provides the first line of defense inflammation is a profound characteristic in most of the neuro- against host invasion by microbial pathogens (1). Although tropic flaviviral infections, including that of Japanese encephalitis I by guest on September 25, 2021 this protective response elicited by the body operates to ensure virus (JEV) (4). JEV is a mosquito-borne ssRNA virus that belongs clearance of detrimental stimuli, an excessive inflammatory re- to the Flaviviridae family, which also includes dengue, Zika, sponse against pathogens can give rise to pathological conditions and West Nile. After entering the body, JEV invades the CNS, resulting into development of signs and symptoms such as fever, headache, and vomiting. About one-third of patients die, and al- *National Brain Research Centre, Manesar, Haryana 122052, India; and †Department of most half of the survivors suffer from permanent cognitive im- Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore pairment (5). Albeit JEV-induced encephalitis is considered to be 560029, India the most prevalent viral encephalitis in the Asia–Pacific region, ORCIDs: 0000-0002-4837-1463 (A.M.); 0000-0002-5200-2054 (A.B.). incidences of the same have been reported nowadays across areas Received for publication January 3, 2019. Accepted for publication August 20, 2019. where the threat was previously unknown and has become the This work was supported by research grants from the Department of Biotechnology cause of worldwide pandemics (6). (BT/PR22341/MED/122/55/2016) and the Tata Innovation Fellowship (BT/HRD/35/ 01/02/2014) to A.B. During the course of infection, JEV entry in the CNS culminates A.B. and B.H. designed the study, generated the hypothesis, analyzed the data, and into massive inflammatory response in the cerebrospinal fluid (7). wrote the manuscript. B.H. and S.C. performed the experiments, interpreted the Although this response appears to play a defensive role against results, and wrote the manuscript. B.H. performed the statistical analysis. M.B. and virus, uncontrolled inflammatory response upon virus infection S.M. performed the experiments. A.M. provided the autopsied human brain sections and reviewed the manuscript. plays a major role in triggering the death of neurons as a bystander Address correspondence and reprint requests to Dr. Anirban Basu, National Brain effect (4, 8). Being a resident macrophage, microglia is considered Research Centre, Manesar, Haryana 122052, India. E-mail address: [email protected] to be the main effector of CNS inflammation, and production The online version of this article contains supplemental material. of various proinflammatory mediators in JEV infection has been Abbreviations used in this article: anti–miR-Con, anti–miR control; CBA, cyto- implicated in the process of microglial activation (9–12). metric bead array; Con-esiRNA, esiRNA control; COX-2, cyclooxygenase-2; DIG, MicroRNAs (miRNAs) are small RNA molecules of 21–22-nt digoxigenin; esiRNA, endoribonuclease-prepared small interfering RNA; FFPE, length that act as important regulators of gene expression (13). formalin-fixed, paraffin embedded; iNOS, inducible NO synthase; IRF1, IFN reg- ulatory factor 1; ISH, in situ hybridization; JEV, Japanese encephalitis virus; LNA, They act at the posttranscriptional level by targeting the 3ʹ locked nucleic acid; MI, mock infection, mock-infected; miR-301a–VM, miR-301a untranslated region (UTR) of mRNAs, resulting in translational Vivo-Morpholino; miRNA, microRNA; MOI, multiplicity of infection; NBRC, National Brain Research Centre; NKRF, NF-kB–repressing factor; NKRF esiRNA, esiRNA repression or degradation of the target. In addition to diverse specific for NKRF; PCNA, proliferating cell nuclear Ag; qRT-PCR, quantitative physiological processes, studies demonstrate miRNAs playing a RT-PCR; snRNA, small nuclear RNA; SOCS5, suppressor of cytokine signaling 5; UTR, vital role in the development of various pathological conditions untranslated region; VM-NC, Vivo-Morpholino negative control; WT, wild-type. (14, 15). Accumulating evidence suggests a decisive role for Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 miRNAs in various neuroinflammatory diseases (16, 17), including www.jimmunol.org/cgi/doi/10.4049/jimmunol.1900003 2 miR-301a REGULATES JEV-INDUCED MICROGLIAL ACTIVATION viral encephalitis (18, 19). Recently, two miRNAs, miR-15b and 8 3 104 cells/cm2. The cells were then incubated at 37˚C and used for miR-19b-3p, have been reported to involve in astrocyte mediated further experiments. neuroinflammation in JEV infection (20, 21). Previously, our Virus propagation and titration group evaluated the effect of JEV infection on the profile of microglial miRNAs, which are reported to be playing important The GP78 strain of JEV was propagated in suckling BALB/c mice (postnatal day 2) of either sex. Following the onset of symptoms, the mice role in regulating the inflammatory response (19). Among the were sacrificed to collect the infected brains. Viral suspension was prepared miRNAs whose expression were modulated upon JEV infection, as reported earlier (18) and stored at 280˚C until needed for use. Viral we already reported the regulatory mechanism of two host miRNAs, titers in culture medium of cell lines and brain samples were assessed by miR-29b and miR-155, in JEV-induced microglial inflammation plaque assay. Plaque formation was performed on monolayers of porcine stable kidney cells as previously mentioned (24). (18, 19). In the current study, miR-301a, which was found to be increased in previous miRNA profiling data, was subjected to Viral infection of cells further investigation to decipher its role in JEV-triggered neuro- All cells were seeded at the desired density in culture plates as per the re- inflammation.
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