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Modulation of miRNA-155 alters manganese nanoparticle-induced inflammatory response.

ABSTRACT: Regulation of gene expression by non-coding RNAs, such as microRNAs (miRNAs), is increasingly being examined in a variety of disciplines. Here we evaluated changes in miRNA expression following metallic nanoparticle (NP) exposure in a mouse neuronal co-culture model. Exposure to manganese (Mn) NPs resulted in oxidative stress, inflammation, and toxicity. Next-generation sequencing (NGS) following an 8 h exposure to Mn NPs (low and high doses) revealed several miRNA candidates that modulate NP induced responses. The lead candidate identified was miR-155, which showed a dose dependent decrease in expression upon Mn exposure. Introduction of a miR-155 mimic into the co-culture to restore miR-155 expression completely abrogated the Mn NP-induced gene and protein expression of inflammatory markers TNF-? and IL-6. Taken together, this study is the first report where global NP-induced miRNA expression changes were used to identify and then modulate negative impacts of metallic NP exposure in a neuronal model. These findings demonstrate that unique miRNA expression profiles provide novel targets for manipulating gene and protein expression, and therefore provide the potential of modifying cellular responses to NP exposure.

SUBMITTER: Grogg MW

PROVIDER: S-EPMC6062203 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Modulation of miRNA-155 alters manganese nanoparticle-induced inflammatory response.

Grogg Matthew W MW Braydich-Stolle Laura K LK Maurer-Gardner Elizabeth I EI Hill Natasha T NT Sakaram Suraj S Kadakia Madhavi P MP Hussain Saber M SM

Toxicology research 20161013 6

Regulation of gene expression by non-coding RNAs, such as microRNAs (miRNAs), is increasingly being examined in a variety of disciplines. Here we evaluated changes in miRNA expression following metallic nanoparticle (NP) exposure in a mouse neuronal co-culture model. Exposure to manganese (Mn) NPs resulted in oxidative stress, inflammation, and toxicity. Next-generation sequencing (NGS) following an 8 h exposure to Mn NPs (low and high doses) revealed several miRNA candidates that modulate NP in ...[more]

PMID: 30090472

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Project description:BackgroundMicroRNA miR-155 is implicated in modulation of the inflammatory processes in various pathological conditions. In our previous studies, we demonstrated that in vivo inhibition of miR-155 promotes functional recovery after mouse experimental stroke. In the present study, we explored if this beneficial effect is associated with miR-155 inhibition-induced alterations in post-stroke inflammatory response.MethodsIntravenous injections of a specific miR-155 inhibitor were initiated at 48 h after mouse distal middle cerebral artery occlusion (dMCAO). Temporal changes in the expression of cytokines and key molecules associated with cytokine signaling were assessed at 7, 14, and 21 days after dMCAO, using mouse cytokine gene and protein arrays and Western blot analyses. Electron and immunofluorescence confocal microscopy techniques were used to evaluate the ultrastructural changes, as well as altered expression of specific phenotypic markers, at different time points after dMCAO.ResultsIn the inhibitor-injected mice (inhibitor group), there was a significant decrease in CCL12 and CXCL3 cytokine expression at 7 days and significantly increased levels of major cytokines IL-10, IL-4, IL-6, MIP-1α, IL-5, and IL-17 at 14 days after dMCAO. These temporal changes correlated with altered expression of miR-155 target proteins SOCS-1, SHIP-1, and C/EBP-β and phosphorylation levels of cytokine signaling regulator STAT-3. Electron microscopy showed decreased number of phagocytically active peri-vascular microglia/macrophages in the inhibitor samples. Immunofluorescence and Western blot of these samples demonstrated that expression of leukocyte/ macrophage marker CD45 and phagocytosis marker CD68 was reduced at 7 days, and in contrast, significantly increased at 14 days after dMCAO, as compared to controls.ConclusionsBased on our findings, we propose that in vivo miR-155 inhibition following mouse stroke significantly alters the time course of the expression of major cytokines and inflammation-associated molecules, which could influence inflammation process and tissue repair after experimental cerebral ischemia.

Project description:MicroRNAs (miRNAs) are single-stranded small RNA molecules that regulate various cellular processes. miRNA 155 (miR-155) regulates various aspects of innate and adaptive immune responses and plays a key role in various viral infections and the resulting neuroinflammation. The present study evaluated the involvement of miR-155 in modulating Japanese encephalitis virus (JEV)-induced neuroinflammation. We observed that miR-155 expression was upregulated during JEV infection of mouse primary microglia, the BV-2 microglia cell line, and in both mouse and human brains. In vitro and in vivo knockdown of miR-155 minimized JEV-induced inflammatory responses. In the present study, we confirmed targeting of the Src homology 2-containing inositol phosphatase 1 (SHIP1) 3' untranslated region (UTR) by miR-155 in the context of JEV infection. Inhibition of SHIP1 by miR-155 resulted in higher beta interferon (IFN-?) and proinflammatory cytokine production through activation of TANK-binding kinase 1 (TBK-1). Based on these observations, we conclude that miR-155 modulates the neuroinflammatory response during JEV infection via negative regulation of SHIP1 expression. Thus, modulation of miR-155 could be a novel strategy to regulate JEV-induced neuroinflammation.Japanese encephalitis virus (JEV), a member of the family Flaviviridae that causes Japanese encephalitis (JE), is the most common mosquito-borne encephalitis virus in the Asia-Pacific region. The disease is feared, as currently there are no specific antiviral drugs available. JEV targets the central nervous system, leading to high mortality and neurological and psychiatric sequelae in some of those who survive. The level of inflammation correlates well with the clinical outcome in patients. Recently, microRNA (miRNA), a single-stranded noncoding RNA, has been implicated in various brain disorders. The present study investigates the role of miRNA in JEV-induced neuroinflammation. Our results show that miRNA 155 (miR-155) targets the Src homology 2-containing inositol phosphatase 1 (SHIP1) protein and promotes inflammation by regulating the NF-?B pathway, increasing the expression of various proinflammatory cytokines and the antiviral response. Thus, miR-155 is a potential therapeutic target to develop antivirals in JE and other brain disorders where inflammation plays a significant role in disease progression.

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Modulation of miRNA-155 alters manganese nanoparticle-induced inflammatory response.

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Modulation of miRNA-155 alters manganese nanoparticle-induced inflammatory response.

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