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miRNA expression profiles and molecular networks in resting and LPS-activated BV-2 microglia-Effect of cannabinoids.
PLoS One. 2019; 14(2):e0212039.Plos

Abstract

Mammalian microRNAs (miRNAs) play a critical role in modulating the response of immune cells to stimuli. Cannabinoids are known to exert beneficial actions such as neuroprotection and immunosuppressive activities. However, the underlying mechanisms which contribute to these effects are not fully understood. We previously reported that the psychoactive cannabinoid Δ9-tetrahydrocannabinol (THC) and the non-psychoactive cannabidiol (CBD) differ in their anti-inflammatory signaling pathways. Using lipopolysaccharide (LPS) to stimulate BV-2 microglial cells, we examined the role of cannabinoids on the expression of miRNAs. Expression was analyzed by performing deep sequencing, followed by Ingenuity Pathway Analysis to describe networks and intracellular pathways. miRNA sequencing analysis revealed that 31 miRNAs were differentially modulated by LPS and by cannabinoids treatments. In addition, we found that at the concentration tested, CBD has a greater effect than THC on the expression of most of the studied miRNAs. The results clearly link the effects of both LPS and cannabinoids to inflammatory signaling pathways. LPS upregulated the expression of pro-inflammatory miRNAs associated to Toll-like receptor (TLR) and NF-κB signaling, including miR-21, miR-146a and miR-155, whereas CBD inhibited LPS-stimulated expression of miR-146a and miR-155. In addition, CBD upregulated miR-34a, known to be involved in several pathways including Rb/E2f cell cycle and Notch-Dll1 signaling. Our results show that both CBD and THC reduced the LPS-upregulated Notch ligand Dll1 expression. MiR-155 and miR-34a are considered to be redox sensitive miRNAs, which regulate Nrf2-driven gene expression. Accordingly, we found that Nrf2-mediated expression of redox-dependent genes defines a Mox-like phenotype in CBD treated BV-2 cells. In summary, we have identified a specific repertoire of miRNAs that are regulated by cannabinoids, in resting (surveillant) and in LPS-activated microglia. The modulated miRNAs and their target genes are controlled by TLR, Nrf2 and Notch cross-talk signaling and are involved in immune response, cell cycle regulation as well as cellular stress and redox homeostasis.

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Authors+Show Affiliations

Juknat A
The Dr Miriam and Sheldon G. Adelson Center for the Biology of Addictive Diseases, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.
Gao F
Departments of Psychiatry and Neurology, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA, United States of America.
Coppola G
Departments of Psychiatry and Neurology, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA, United States of America.
Vogel Z
The Dr Miriam and Sheldon G. Adelson Center for the Biology of Addictive Diseases, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.
Kozela E
The Dr Miriam and Sheldon G. Adelson Center for the Biology of Addictive Diseases, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.

MeSH

AnimalsCannabidiolCannabinoidsCell LineDronabinolGene Expression ProfilingGene Expression RegulationGene Regulatory NetworksHigh-Throughput Nucleotide SequencingLipopolysaccharidesMiceMicroRNAsMicrogliaSequence Analysis, RNA

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30742662

Citation

Juknat, Ana, et al. "MiRNA Expression Profiles and Molecular Networks in Resting and LPS-activated BV-2 microglia-Effect of Cannabinoids." PloS One, vol. 14, no. 2, 2019, pp. e0212039.
Juknat A, Gao F, Coppola G, et al. MiRNA expression profiles and molecular networks in resting and LPS-activated BV-2 microglia-Effect of cannabinoids. PLoS One. 2019;14(2):e0212039.
Juknat, A., Gao, F., Coppola, G., Vogel, Z., & Kozela, E. (2019). MiRNA expression profiles and molecular networks in resting and LPS-activated BV-2 microglia-Effect of cannabinoids. PloS One, 14(2), e0212039. https://doi.org/10.1371/journal.pone.0212039
Juknat A, et al. MiRNA Expression Profiles and Molecular Networks in Resting and LPS-activated BV-2 microglia-Effect of Cannabinoids. PLoS One. 2019;14(2):e0212039. PubMed PMID: 30742662.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - miRNA expression profiles and molecular networks in resting and LPS-activated BV-2 microglia-Effect of cannabinoids. AU - Juknat,Ana, AU - Gao,Fuying, AU - Coppola,Giovanni, AU - Vogel,Zvi, AU - Kozela,Ewa, Y1 - 2019/02/11/ PY - 2018/08/02/received PY - 2019/01/25/accepted PY - 2019/2/12/entrez PY - 2019/2/12/pubmed PY - 2019/11/9/medline SP - e0212039 EP - e0212039 JF - PloS one JO - PLoS One VL - 14 IS - 2 N2 - Mammalian microRNAs (miRNAs) play a critical role in modulating the response of immune cells to stimuli. Cannabinoids are known to exert beneficial actions such as neuroprotection and immunosuppressive activities. However, the underlying mechanisms which contribute to these effects are not fully understood. We previously reported that the psychoactive cannabinoid Δ9-tetrahydrocannabinol (THC) and the non-psychoactive cannabidiol (CBD) differ in their anti-inflammatory signaling pathways. Using lipopolysaccharide (LPS) to stimulate BV-2 microglial cells, we examined the role of cannabinoids on the expression of miRNAs. Expression was analyzed by performing deep sequencing, followed by Ingenuity Pathway Analysis to describe networks and intracellular pathways. miRNA sequencing analysis revealed that 31 miRNAs were differentially modulated by LPS and by cannabinoids treatments. In addition, we found that at the concentration tested, CBD has a greater effect than THC on the expression of most of the studied miRNAs. The results clearly link the effects of both LPS and cannabinoids to inflammatory signaling pathways. LPS upregulated the expression of pro-inflammatory miRNAs associated to Toll-like receptor (TLR) and NF-κB signaling, including miR-21, miR-146a and miR-155, whereas CBD inhibited LPS-stimulated expression of miR-146a and miR-155. In addition, CBD upregulated miR-34a, known to be involved in several pathways including Rb/E2f cell cycle and Notch-Dll1 signaling. Our results show that both CBD and THC reduced the LPS-upregulated Notch ligand Dll1 expression. MiR-155 and miR-34a are considered to be redox sensitive miRNAs, which regulate Nrf2-driven gene expression. Accordingly, we found that Nrf2-mediated expression of redox-dependent genes defines a Mox-like phenotype in CBD treated BV-2 cells. In summary, we have identified a specific repertoire of miRNAs that are regulated by cannabinoids, in resting (surveillant) and in LPS-activated microglia. The modulated miRNAs and their target genes are controlled by TLR, Nrf2 and Notch cross-talk signaling and are involved in immune response, cell cycle regulation as well as cellular stress and redox homeostasis. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/30742662/miRNA_expression_profiles_and_molecular_networks_in_resting_and_LPS_activated_BV_2_microglia_Effect_of_cannabinoids_ DB - PRIME DP - Unbound Medicine ER -