Modulation of Immune Responses by Small Regulatory RNA in Mammalian Macrophages
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
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| Title |
Modulation of Immune Responses by Small Regulatory RNA in Mammalian Macrophages
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| Creator |
Mazumdar, Anup
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| Subject |
Molecular & Human Genetics
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| Description |
Innate immune response provides the first line of defence in mammalian immune system. The innate immune response can be of two types: pro-inflammatory and anti-inflammatory. Activation with lipopolysaccharide (LPS) induces expression of pro-inflammatory cytokines in mammalian macrophages whereas infection with protozoan parasite Leishmania induces anti-inflammatory immune response. miRNAs are the tiny regulators of gene expression in metazoan. In monocytes and macrophages, miRNAs play a key regulatory role in controlling immune responses as expression of a number of cytokines is regulated by miRNAs. Upon macrophage activation, the pro-inflammatory cytokine mRNAs are rapidly translated, although expression of most of the miRNAs targeting these mRNAs remains largely unaltered. Therefore, to be translated in activated cells, the cytokine mRNAs must be protected from miRNA-mediated repression. But how these mRNAs become immune to miRNAs is unknown. We show that there is a transient reversal of miRNA-mediated repression during the early phase of pro-inflammatory response in macrophages, which leads to protection of cytokine mRNAs from miRNA-mediated repression. This derepression is caused by impaired miRNA binding to Ago2 protein, a key component of miRNP complex. In activated macrophage, Ago2 protein gets phosphorylated at Y529 position in a reversible manner affecting miRNA as well as target mRNA binding. Macrophages expressing mutant Ago2, that cannot be phosphorylated and thus remains bound to miRNAs and target mRNAs, showed weaken pro-inflammatory response and failed to prevent parasite invasion. We have also found that during longer incubation of LPS or during Leishmania donovani infection, a phosphatase PP2A dephosphorylates Ago2 to keep the miRISC active.The active miRISC then represses the pro-inflammatory cytokines. This helps activated macrophage to fine tune cytokine response to avoid hyper responsiveness at later stage of LPS stimulation. In infection model this helps Leishmania to evade pro-inflammatory immune response and to survive inside the macrophages.
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| Date |
2014
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| Type |
Thesis
NonPeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/2085/1/THESIS__ANUP_MAZUMDER.pdf
Mazumdar, Anup (2014) Modulation of Immune Responses by Small Regulatory RNA in Mammalian Macrophages. PhD thesis, Calcutta University. |
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| Relation |
http://www.eprints.iicb.res.in/2085/
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