Invited ReviewMicroRNAs mediating CNS inflammation: Small regulators with powerful potential
Section snippets
Microglia
Microglia are the specialized resident innate immune cells of the central nervous system (CNS) that play essential roles in development, plasticity and immune surveillance. While innate immune cell function is generally studied in response to injury or pathogen exposure, microglia have been demonstrated to participate in a variety of homeostatic roles in the developing and adult CNS. During homeostasis, microglia may act as sensors of environmental change and perform essential functions
MicroRNA
MicroRNAs (miRNAs) are a growing class of small non-coding RNAs (∼22 nucleotides) that regulate gene expression post-transcriptionally by targeting the 3′ untranslated region (3′UTR) of messenger RNAs (mRNAs). The nomenclature and classification schemes for miRNAs have not yet been finalized, however it is generally considered that miRNAs with identical sequences at nucleotides 2–8 of the mature miRNA belong to the same ‘miRNA family’ (Bartel, 2009). Although first discovered in the early 1990s
MicroRNAs in the CNS
To date, miRNAs are the smallest identified ribonucleic acid carriers of highly specific, genetic regulatory information. They are the most abundant extracellular, highly soluble nucleic acids present in multiple human circulatory fluids and serum, and are capable of spreading genetic signaling information, both homeostatic and pathogenic, among neighboring CNS cells and tissues. Compared with other organs, the brain has a particularly high percentage of tissue-specific and tissue-enriched
miRNA regulation of CNS inflammation
In addition to their well-studied roles in CNS cell fate determination, several studies have shown that miRNAs regulate both innate and adaptive immune responses (Baltimore et al., 2008). miRNAs play significant roles in inflammatory activation and the resolution of the phasic pro-inflammatory response as diagramed in Fig. 1. Some well-studied miRNA modulators of inflammation have been evaluated in cultured microglia and have been identified as either promoting pro-inflammatory behaviors or
miR-155
miR-155 was identified as a B cell integration cluster (bic), which induces B cell leukosis in chickens following activation through viral promoter insertion (Eis et al., 2005). Subsequent studies have shown that transgenic overexpression of miR-155 in B cells generated lymphoma, suggesting that miR-155 is oncogenic (Mashima, 2015). In addition, miR-155 was shown to be upregulated in macrophages, monocytes, and microglia in response to several pro-inflammatory stimuli, such as LPS, IFN-γ, and
miR-145
miR-145 was first recognized as a tumor suppressor miRNA that is transcriptionally regulated by p53 and is often co-expressed with miR-143 (Chen et al., 2010). miR-143 and miR-145 form a bicistronic cluster in 5q33.1 region and these two miRNAs have been extensively studied for their role in neoplastic pathways in epithelial cell malignancies (Kent et al., 2014). miR-143/miR-145 was involved in the phenotypic switch of vascular smooth muscle cells and has been associated with atherosclerosis.
miR-146
The miR-146 miRNA family consists of two evolutionary conserved miRNA genes: miR-146a and miR-146b (Boldin et al., 2011). miR-146a is an inducible, NF-κB-regulated miRNA ubiquitously expressed in microglia and astrocytes of the brain and retina (Alexandrov et al., 2014, Boldin et al., 2011, Li et al., 2011). The 5′ regulatory region of the miR-146a gene harbors NF-κB binding sites and its expression is upregulated by pro-inflammatory signals (Lukiw et al., 2008).
Alterations in expression of
Interactions between miR-155 and miR-146 may contribute to microglia activation in disease
Emerging evidence shows that miRNAs can work together and play critical regulatory roles that affect neuroimmune functions. miR-155 and miR-146a are commonly shown to act together in modulation of different stages of the innate immune response during inflammation and infection (Elton et al., 2013, O’Connell et al., 2010). Both miR-155 and miR-146a seem to play a fundamental role in the microglial inflammatory profile. While miR-146a acts as a negative regulator of inflammation by suppressing
miRNAs regulating inflammatory responses are involved in behavior and disease
The role of miRNAs in neurological disease has been extensively studied. Altered expression of miRNAs has been shown to be not only responsible for gene expression changes, but also for inducing disease phenotypes including cancer, metabolic disorders and neurological abnormalities. Therefore, use of miRNAs as a disease biomarker and potential therapeutic targets has been strongly advocated.
One recent example of a miRNA biomarker was employed in a study of post-stroke depression (PSD) (Zeng et
Conclusions and future directions
The above-mentioned results highlight the prominent role of miRNAs in the regulation of inflammatory responses in the CNS and suggest new possibilities for development of anti-inflammatory therapies. Although the precise contribution of microglia to CNS inflammation and neurodegeneration remains to be fully elucidated, targeting the behavior of microglia has been suggested as a potential novel therapeutic strategy for a wide variety of CNS disorders. Microglia function could be directed toward
Acknowledgments
The efforts of the authors on this manuscript were funded by the National Institutes of Health − United States (R01NS073848-G.A.G. and W.S., and T32GM095421-M.S.A.)
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