Involvement of microRNA in microglia-mediated immune response.

Hindawi Publishing Corporation Clinical and Developmental Immunology Volume 2013, Article ID 186872, 11 pages http://dx.doi.org/10.1155/2013/186872 Review Article Involvement of MicroRNA in Microglia-Mediated Immune Response J. Guedes,1,2 A. L. C. Cardoso,3 and M. C. Pedroso de Lima3,4 1 PhD Programme in Experimental Biology and Biomedicine (PDBEB), CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal 2 Institute for Interdisciplinary Research (IIIUC), University of Coimbra, 3030-789 Coimbra, Portugal 3 CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal 4 Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, 3001-401 Coimbra, Portugal Correspondence should be addressed to M. C. Pedroso de Lima; Received 21 March 2013; Accepted 8 May 2013 Academic Editor: Anirban Basu Copyright © 2013 J. Guedes et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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. 1. Introduction Microglia cells are crucial for the development and maintenance of the central nervous system (CNS). In addition to acting as sensors of environmental changes that precede pathological events, these cells have been shown to support neuronal function by monitoring synaptic activity, controlling synaptogenesis, and promoting neuronal apoptosis during development [1–3]. Although they are considered one of the four major cellular types of the CNS, they do not originate from the same precursor cells as astrocytes, oligodendrocytes, or neurons. Instead, they derive from myeloid progenitor cells and share several markers with peripheral monocytes, macrophages, and dendritic cells, such as CD11b, F4/80, and CD45 [4]. The first resident parenchymal microglia cells are believed to originate from yolk sac immature macrophages in early stages of fetal development. In humans, microglia precursor cells arrive at the brain in two waves during the first and second trimester of gestation, while in rodents this migration occurs shortly before and after birth. The sudden increase in CD11b+ and F4/80+ cells observed in the early postnatal period in rodents was until recently attributed to the recruitment of bone marrow derived cells, suggesting that myeloid precursors could also contribute to the initial pool of microglia cells in the CNS. However, most of the studies supporting these findings used irradiation of the recipient animals to allow bone marrow engraftment of genetically-labeled cells [5], which was later found to strongly influence the observed results [6]. In 2010, Ginhoux and colleagues shed light on the origin of microglia. The authors performed in vivo lineage tracing studies using Cre recombinase activity, which was induced into pregnant mice between days 7 and 8 of fetal development, when embryonic hematopoiesis is restricted to the yolk sac. The results from 2 this study clearly demonstrated that postnatal hematopoietic progenitors do not contribute significantly to microglia postnatal numbers and that the cellular expansion observed in this period is mainly dependent on the proliferation of the resident yolk sac-derived microglia population [7]. The question remains whether this is also true in the adult brain, especially following a neurological insult or in the case of a neurodegenerative disease, wherein the integrity of the blood-brain barrier (BBB) may be compromised. Several studies have shown that the infiltration of bone marrow-derived cells into the brain is possible under those circumstances and may even play a central role in disease modulation. Nevertheless, the exact nature of the contribution of parenchymal and blood-derived microglia to the neuroimmune response, in the context of neuronal disease, remains to be clarified [8–10]. Following their migration to the neuronal tissue, microglia cells assume a surveying phenotype, usually referred as “resting microglia,” characterized by a small and static cell body, a large number of highly motile ramifications, and low expression of macrophage-related surface markers, such as the major histocompatibility complex II (MHC II) and CD45 [11]. The low levels of these markers distinguish parenchymal “resting” microglia from peripheral macrophages. However, following a neuronal insult, such as ischemia, infection, and trauma or in the presence of inflammatory mediators (IFN-𝛾), microglia cells assume an amoeboid form, losing their ramifications, and overexpressing the above-mentioned markers. This process is referred to as microglia “activation” and is known to induce profound phenotypical changes, making parenchymal microglia to become almost indistinguishable from peripheral macrophages [11]. Similarly to what has been described in macrophages, microglia activation can also originate different subsets of cells, depending on the nature of the activating stimulus and surrounding environment. These different activation phenotypes express distinct molecular markers and exert different functions in the neuronal tissue [12]. The definition of the different activation states of macrophages was initially based on the expression of proinflammatory receptors and cytokines (M1 phenotype—classical activation) or on the expression of anti-inflammatory receptors and cytokines (M2 phenotype—alternative activation). Further studies revealed the existence of several intermediate activation s (...truncated)