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Involvement of MicroRNA in Microglia-Mediated Immune Response

Guedes, J., Cardoso, A. L. C., Pedroso de Lima, M. C.·2013·Clinical and Developmental Immunology
DOI 10.1155/2013/186872PMC PMC3676986
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Abstract

MicroRNAs (miRNAs) are an abundant class of small noncoding RNA molecules that play an important role in the regulation of gene expression at the posttranscriptional level. Due to their ability to simultaneously modulate the fate of different genes, these molecules are particularly well suited to act as key regulators during immune cell differentiation and activation, and their dysfunction can contribute to pathological conditions associated with neuroinflammation. Recent studies have addressed the role of miRNAs in the differentiation of progenitor cells into microglia and in the activation process, aiming at clarifying the origin of adult microglia cells and the contribution of the central nervous system (CNS) environment to microglia phenotype, in health and disease. Altered expression of several miRNAs has been associated with Alzheimer’s disease, multiple sclerosis, and ischemic injury, hence strongly advocating the use of these small molecules as disease markers and new therapeutic targets. This review summarizes the recent advances in the field of miRNA-mediated regulation of microglia development and activation. We discuss the role of specific miRNAs in the maintenance and switching of microglia activation states and illustrate the potential of this class of nucleic acids both as biomarkers of inflammation and new therapeutic tools for the modulation of microglia behavior in the CNS.

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Figure 1 MiRNA contribution to microglia activation phenotypes. Resting microglia cells are characterized by low expression levels of miR-155 and a relatively high expression of miR-124. In the presence of strong inflammatory stimuli, such as IFN-γ, GM-CSF, and LPS, microglia assume a classical activation phenotype (M1), characterized by the upregulation of both CD45 and MHC II, the expression of several inflammatory mediators, such as iNOS, the inflammatory cytokines IL-6 and TNF-α, the type I interferon IFN-β, and the downregulation of miR-124. MiR-155 upregulation is thought to be crucial for the establishment of this phenotype, since this miRNA directly targets several anti-inflammatory molecules, including SOCS-1. Alternatively, in the presence of TGF-β or the anti-inflammatory cytokine IL-10, a different activation phenotype is observed (M2). In this case, CD206 is upregulated at the cell surface, and anti-inflammatory molecules involved in tissue repair and angiogenesis are expressed. Moreover, most proinflammatory pathways, including those regulated by the transcription factors c-Jun and NF-κB, are inactivated, and miR-155 upregulation is not observed. Certain endogenous danger signals associated with neurodegenerative disorders, such as Aβ fibrils present in senile plaques of AD patients, can also cause microglia activation, although the exact nature of the observed phenotypic changes is yet to be fully characterized.
Figure 1 MiRNA contribution to microglia activation phenotypes. Resting microglia cells are characterized by low expression levels of miR-155 and a relatively high expression of miR-124. In the presence of strong inflammatory stimuli, such as IFN-γ, GM-CSF, and LPS, microglia assume a classical activation phenotype (M1), characterized by the upregulation of both CD45 and MHC II, the expression of several inflammatory mediators, such as iNOS, the inflammatory cytokines IL-6 and TNF-α, the type I interferon IFN-β, and the downregulation of miR-124. MiR-155 upregulation is thought to be crucial for the establishment of this phenotype, since this miRNA directly targets several anti-inflammatory molecules, including SOCS-1. Alternatively, in the presence of TGF-β or the anti-inflammatory cytokine IL-10, a different activation phenotype is observed (M2). In this case, CD206 is upregulated at the cell surface, and anti-inflammatory molecules involved in tissue repair and angiogenesis are expressed. Moreover, most proinflammatory pathways, including those regulated by the transcription factors c-Jun and NF-κB, are inactivated, and miR-155 upregulation is not observed. Certain endogenous danger signals associated with neurodegenerative disorders, such as Aβ fibrils present in senile plaques of AD patients, can also cause microglia activation, although the exact nature of the observed phenotypic changes is yet to be fully characterized.CC BY · PubMed Central
Figure 2 MiR-155 inhibition in microglia cells increases SOCS-1 levels and decreases the release of inflammatory cytokines to the extracellular medium. N9 mouse microglia cells were transfected with anti-miR-155 oligonucleotides (anti-miR155) or with nontargeting oligonucleotides (oligo scramble) complexed with cationic liposomes for 4 h. Twenty-four hours after transfection, cells were incubated with LPS at 0.1 μg/mL for 18 h. The cell culture medium was then collected to determine cytokine protein levels, and total RNA was extracted from the cultured cells. (a) SOCS-1 mRNA levels were quantified by qRT-PCR. (b) The levels of TNF-α, IL-1β, and IL-6 secreted to the cultured medium were determined by ELISA. Results are expressed as fold change of mRNA or protein levels with respect to control (untransfected and untreated cells). **P < 0.01 compared to cells transfected with the scramble oligonucleotide and ***P < 0.01 compared to LPS-treated cells in the absence of transfection. Results in (a) and (b) are representative of 3 independent experiments performed in triplicate.
Figure 2 MiR-155 inhibition in microglia cells increases SOCS-1 levels and decreases the release of inflammatory cytokines to the extracellular medium. N9 mouse microglia cells were transfected with anti-miR-155 oligonucleotides (anti-miR155) or with nontargeting oligonucleotides (oligo scramble) complexed with cationic liposomes for 4 h. Twenty-four hours after transfection, cells were incubated with LPS at 0.1 μg/mL for 18 h. The cell culture medium was then collected to determine cytokine protein levels, and total RNA was extracted from the cultured cells. (a) SOCS-1 mRNA levels were quantified by qRT-PCR. (b) The levels of TNF-α, IL-1β, and IL-6 secreted to the cultured medium were determined by ELISA. Results are expressed as fold change of mRNA or protein levels with respect to control (untransfected and untreated cells). **P < 0.01 compared to cells transfected with the scramble oligonucleotide and ***P < 0.01 compared to LPS-treated cells in the absence of transfection. Results in (a) and (b) are representative of 3 independent experiments performed in triplicate.CC BY · PubMed Central

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Metadata

Authors
Guedes, J., Cardoso, A. L. C., & Pedroso de Lima, M. C.
Affiliations
  • PhD Programme in Experimental Biology and Biomedicine (PDBEB), CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal
  • CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal
Venue
Clinical and Developmental Immunology
Publisher
Wiley
Published
2013
Volume
2013
Pages
1-11
ISSN
  • 1740-2522
  • 1740-2530
DOI
10.1155/2013/186872
PMC
PMC3676986
Cited by
65
References
20
Language
en
Licence
creativecommons.org/licenses/by/3.0/ (unspecified)
Funders
  • Fundação para a Ciência e a Tecnologia (PTDC/BIM-MEC/0651/2012, Pest-C/SAU/LA0001/2011, SFRH/BD/51677/2011, SFRH/BPD/46228/2008)
  • FEDER/COMPETE (PTDC/BIM-MEC/0651/2012, Pest-C/SAU/LA0001/2011, SFRH/BD/51677/2011, SFRH/BPD/46228/2008)

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