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      Micromanagement of Immune System: Role of miRNAs in Helminthic Infections

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          Abstract

          Helminthic infections fall under neglected tropical diseases, although they inflict severe morbidity to human and causes major economic burden on health care system in many developing countries. There is increased effort to understand their immunopathology in recent days due to their immuno-modulatory capabilities. Immune response is primarily controlled at the transcriptional level, however, microRNA-mediated RNA interference is emerging as important regulatory machinery that works at the translation level. In the past decade, microRNA (miRNA/miR) research has advanced with significant momentum. The result is ever increasing list of curated sequences from a broad panel of organisms including helminths. Several miRNAs had been discovered from trematodes, nematodes and cestodes like let-7, miR155, miR-199, miR-134, miR-223, miR-146, and fhe-mir-125a etc., with potential role in immune modulation. These miRs had been associated with TGF-β, MAPK, Toll-like receptor, PI3K/AKT signaling pathways and insulin growth factor regulation. Thus, controlling the immune cells development, survival, proliferation and death. Apart from micromanagement of immune system, they also express certain unique miRNA also like cis-miR-001, cis-miR-2, cis-miR-6, cis-miR-10, cis-miR-18, cis-miR-19, trs-mir-0001, fhe-miR-01, fhe-miR-07, fhe-miR-08, egr-miR-4988, egr-miR-4989 etc. The specific role played by most of these species specific unique miRs are yet to be discovered. However, these newly discovered miRNAs might serve as novel targets for therapeutic intervention or biomarkers for parasitic infections.

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          Most cited references57

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          Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans.

          During C. elegans development, the temporal pattern of many cell lineages is specified by graded activity of the heterochronic gene Lin-14. Here we demonstrate that a temporal gradient in Lin-14 protein is generated posttranscriptionally by multiple elements in the lin-14 3'UTR that are regulated by the heterochronic gene Lin-4. The lin-14 3'UTR is both necessary and sufficient to confer lin-4-mediated posttranscriptional temporal regulation. The function of the lin-14 3'UTR is conserved between C. elegans and C. briggsae. Among the conserved sequences are seven elements that are each complementary to the lin-4 RNAs. A reporter gene bearing three of these elements shows partial temporal gradient activity. These data suggest a molecular mechanism for Lin-14p temporal gradient formation: the lin-4 RNAs base pair to sites in the lin-14 3'UTR to form multiple RNA duplexes that down-regulate lin-14 translation.
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            Regulation of progenitor cell proliferation and granulocyte function by microRNA-223.

            MicroRNAs are abundant in animal genomes and have been predicted to have important roles in a broad range of gene expression programmes. Despite this prominence, there is a dearth of functional knowledge regarding individual mammalian microRNAs. Using a loss-of-function allele in mice, we report here that the myeloid-specific microRNA-223 (miR-223) negatively regulates progenitor proliferation and granulocyte differentiation and activation. miR-223 (also called Mirn223) mutant mice have an expanded granulocytic compartment resulting from a cell-autonomous increase in the number of granulocyte progenitors. We show that Mef2c, a transcription factor that promotes myeloid progenitor proliferation, is a target of miR-223, and that genetic ablation of Mef2c suppresses progenitor expansion and corrects the neutrophilic phenotype in miR-223 null mice. In addition, granulocytes lacking miR-223 are hypermature, hypersensitive to activating stimuli and display increased fungicidal activity. As a consequence of this neutrophil hyperactivity, miR-223 mutant mice spontaneously develop inflammatory lung pathology and exhibit exaggerated tissue destruction after endotoxin challenge. Our data support a model in which miR-223 acts as a fine-tuner of granulocyte production and the inflammatory response.
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              MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-α-PU.1 pathway.

              MicroRNAs are a family of regulatory molecules involved in many physiological processes, including differentiation and activation of cells of the immune system. We found that brain-specific miR-124 is expressed in microglia but not in peripheral monocytes or macrophages. When overexpressed in macrophages, miR-124 directly inhibited the transcription factor CCAAT/enhancer-binding protein-α (C/EBP-α) and its downstream target PU.1, resulting in transformation of these cells from an activated phenotype into a quiescent CD45(low), major histocompatibility complex (MHC) class II(low) phenotype resembling resting microglia. During experimental autoimmune encephalomyelitis (EAE), miR-124 was downregulated in activated microglia. Peripheral administration of miR-124 in EAE caused systemic deactivation of macrophages, reduced activation of myelin-specific T cells and marked suppression of disease. Conversely, knockdown of miR-124 in microglia and macrophages resulted in activation of these cells in vitro and in vivo. These findings identify miR-124 both as a key regulator of microglia quiescence in the central nervous system and as a previously unknown modulator of monocyte and macrophage activation.
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                Author and article information

                Contributors
                Journal
                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                1664-302X
                13 April 2017
                2017
                : 8
                : 586
                Affiliations
                [1] 1School of Basic Sciences, Indian Institute of Technology Mandi Mandi, India
                [2] 2Department of Immunology, Weizmann Institute of Science Rehovot, Israel
                [3] 3Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur Jodhpur, India
                Author notes

                Edited by: Celio Geraldo Freire De Lima,Federal University of Rio de Janeiro, Brazil

                Reviewed by: Fernanda Ferreira Cruz, Federal University of Rio de Janeiro, Brazil; Herbert Leonel de Matos Guedes, Federal University of Rio de Janeiro, Brazil; Theo Araújo-Santos, Federal University of Western Bahia, Brazil; Laura Noelia Cariddi, Universidad Nacional de Río Cuarto, Argentina

                *Correspondence: Amit Prasad, amitprasad@ 123456iitmandi.ac.in

                This article was submitted to Microbial Immunology, a section of the journal Frontiers in Microbiology

                Article
                10.3389/fmicb.2017.00586
                5390025
                28450853
                e5509b29-b75f-40e3-8038-d27b7fae0eb2
                Copyright © 2017 Arora, Tripathi, Singh, Mondal, Mishra and Prasad.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 20 January 2017
                : 21 March 2017
                Page count
                Figures: 2, Tables: 2, Equations: 0, References: 94, Pages: 13, Words: 0
                Funding
                Funded by: Department of Biotechnology, Ministry of Science and Technology 10.13039/501100001407
                Award ID: Ramalingaswami fellowship
                Funded by: Science and Engineering Research Board 10.13039/501100001843
                Award ID: EMR/2016/000716
                Award ID: ECR/2016/000817/LS
                Categories
                Microbiology
                Review

                Microbiology & Virology
                mirna,parasite,helminth,immune-modulation,infection
                Microbiology & Virology
                mirna, parasite, helminth, immune-modulation, infection

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