Review articleMicroRNA 155 and viral-induced neuroinflammation
Introduction
miRNAs are short, non-coding RNA molecules that function to regulate gene expression at the post-transcriptional level by binding complimentary 3′ untranslated region (3′ UTR) sequences of target mRNAs, thereby repressing gene expression (1). miRNAs were first reported in the 1990s as regulatory sequences involved in C. elegans development (Lee et al., 1993); however, they have since been further characterized as gene-repression elements that affect gene-expression profiles in more than 100 animal species (Griffiths-Jones et al., 2006).
The majority of miRNAs are encoded within intron regions of genomes, and are transcribed by RNA polymerase II into primary transcripts referred to as pri-miRNAs. In the canonical miRNA pathway, pri-miRNAs are cleaved by an RNAase III-Drosha complex in order to yield pre-miRNAs. Alternatively, miRNA transcripts called mirtrons are produced independently of the RNAase III-Drosha complex (Kim et al., 2009). Pre-miRNAs and mirtrons are transported from the nucleus by Exportin 5 into the cytoplasm and processed by Dicer into short (~ 22 nucleotides), double-stranded miRNA/miRNA molecules that subsequently form an RNA-induced silencing complex (RISC) with Argonaute and other proteins. In the RISC complex, one strand of the miRNA duplex functions to bind complementary sequences in the 3′UTR and thereby repress target genes, while the other strand is degraded (Dai and Ahmed, 2011). miRNAs are regulated in part by RNA-binding proteins that help determine the context in which miRNAs are available for target-gene repression (van Kouwenhove et al., 2011).
Because miRNAs have been shown to target many important signaling proteins and transcription factors that govern immune processes and differentiation (O'Connell and Baltimore, 2012, O'Connell et al., 2010a), it is not surprising that these molecules have important roles during immune responses to microbial infections, including those that affect the CNS. Infection of the CNS results in significant changes in miRNA expression profiles, many of which facilitate various aspects of immune processes (Dahm et al., 2016, Cardoso et al., 2016). It should be noted that there is a growing body of literature that discusses miRNAs encoded by viruses that influence viral pathogenesis; however, they are beyond the scope of this review. One miRNA that has gained considerable attention in recent years is mammalian-encoded miR-155, which numerous reports have implicated in regulating immune responses, including to neurotropic viruses. Here we provide a discussion of several examples in which miR-155 regulates neuroinflammation during viral infection of the CNS.
While miR-155 was originally identified as an oncogene in chicken lymphomas (Tam et al., 1997), subsequent work has revealed that it has myriad roles in regulating immune responses. miR-155 is overexpressed in some mammalian hematopoietic cancers and is expressed by and functions within a variety of activated immune cell types, including B cells, macrophages, various T cell populations, NK cells, and dendritic cells (Vigorito et al., 2007, Haasch et al., 2002, O'Connell et al., 2007, Rodriguez et al., 2007, Taganov et al., 2006, Thai et al., 2007) to regulate cytokines, chemokines, and transcription factors important for mounting an optimal immune response. For example, miR-155 expression leads to increased production of IFN-γ and diminished expression of IL-2 by T cells (Banerjee et al., 2010, Das et al., 2013, Gracias et al., 2013), augments IFN-γ-dependent CD4+ and CD8+ T cell responses to tumors (Huffaker et al., 2012), contributes to the development of T regulatory cells (Lu et al., 2015, Kohlhaas et al., 2009), and alters the CD8+ T cell memory:effector ratio by skewing CD8+ T cells toward a memory phenotype (Almanza et al., 2010). Within immune cells, miR-155 represses a variety of immunoregulatory proteins that include signaling molecules such as SHIP1 (Trotta et al., 2012) and SOCS1 (Wang et al., 2010), as well as transcriptional regulators such as Jarid2 (Nakagawa et al., 2016), Ets1 (Zhu et al., 2011, Hu et al., 2013), PU.1 (29) and Fosl2 (Hu et al., 2014). Importantly, Moore et al. (2013) showed that miR-155 drives myeloid cells toward an M1, or proinflammatory, phenotype. Several studies suggests that expression of miR-155 by microglia is important in regulating expression of proinflammatory genes that subsequently influence neuroinflammation, primarily though the inhibition of SOCS1 and genes involved in microglial polarization such as IL-13R, SMAD2, and CEBPβ (Cardoso et al., 2016, Freilich et al., 2013, Ponomarev et al., 2013, Su et al., 2016). These and other studies have demonstrated that miR-155 is an important regulator of immune cell development and function.
There is increasing evidence that miR-155 influences neuroinflammatory diseases such as the human demyelinating disease multiple sclerosis. miR-155 was initially shown to influence neuroinflammation through the induction of myelin-reactive Th17 cells following induction of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS) (Murugaiyan et al., 2011, O'Connell et al., 2010b). Alejandro et al. (Lopez-Ramirez et al., 2014) discovered that miR-155 is upregulated in neurovascular units in active MS lesions compared to normal-appearing white matter in MS patients. In addition, the group used the EAE model to show that miR-155 expression is dramatically increased in mice with hind-limb paralysis during the recovery phase, and that miR-155 regulates blood-brain-barrier (BBB) function. The latter finding is consistent with a study by Lopez-Ramirezet al. (2014) showing that miR-155 negatively regulates blood-brain-barrier permeability by targeting the cell-cell complex molecules annexin-2 and claudin1, as well as the adhesion components DOCK-1 and syntenin-1. In a recent study, Cerutti et al. (2016) also demonstrated that miR-155 regulates blood-brain barrier function by targeting adhesion molecules VCAM1 and ICAM1, thereby affecting monocyte and T cell adhesion to the brain endothelium. Roles for miR-155 during neuroinflammation have also been demonstrated in models of Parkinson's Disease (Thome et al., 2016), Alzheimer's Disease (Guedes et al., 2014), alcohol-induced neuroinflammation (Lippai et al., 2013), and amyotrophic lateral sclerosis (ALS) (Parisi et al., 2013).
Not surprisingly, multiple reports identify miR-155 as important in mediating host responses to microbial diseases (Zeng et al., 2015), including viral infections with members of the Herpesviridae, Coronaviridae, Arenaviridae, Flaviviridae, and Retroviridae families (discussed further below) (Yao and Nair, 2014, Kaluzna, 2014, Gottwein, 2013, Bhela et al., 2015, Bhela et al., 2014, Dickey et al., 2016, Dudda et al., 2013, Lind et al., 2013, Lu et al., 2011, Martinez-Nunez et al., 2009, Napuri et al., 2013, Zawislak et al., 2013). Recently, miR-155 has been shown to tailor immune responses in models of viral-induced neurologic disease, and numerous mechanisms by which miR-155 controls immune responses following viral infection have been identified. For example, multiple studies have demonstrated that T cell responses are impaired in the absence of miR-155 during infection with certain neurotropic viruses (Lu et al., 2015, Bhela et al., 2015, Bhela et al., 2014, Dickey et al., 2016, Dudda et al., 2013, Lind et al., 2013, Zawislak et al., 2013). Below, we highlight several examples in which miR-155 influences inflammatory responses following viral infection of the CNS (Table 1).
Section snippets
Herpes simplex virus (HSV)
HSV infections generally result in surface lesions on skin, mucosa, and eyes. After primary infection, HSV establishes a life-long latent infection in neuronal tissues, although latent virus is periodically reactivated. While this process is not thoroughly defined, factors such as fever, UV exposure, increased viral load, stress, and host genetics have been implicated in HSV reactivation (Roizman and Whitley, 2013). Occasionally, HSV spreads to the brain and causes a rare but life-threatening
Conclusions
This review highlights various mechanisms by which miR-155 regulates inflammatory processes in response to viral infections in the CNS. Currently, miR-155 is known to influence virally induced neuroinflammation by regulating CD4+ and CD8+ T cell accumulation, NK cell maturation and expansion, T cell cytokine production, CD8+ T cell-mediated cytotoxicity, astrogliosis, macrophage polarization, expression of receptors necessary for viral entry, and expression of viral proteins. As miRNA-virus
Funding
This work was supported by NIH grant R01 NS041249 to TEL and R01 AG047956 to RMO. LLD is supported by Postdoctoral Fellowship FG20105A1 from the National Multiple Sclerosis Society.
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