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microRNA-mediated regulation of innate immune response in rheumatic diseases.

Luo X, Ranade K, Talker R, Jallal B, Shen N, Yao Y - Arthritis Res. Ther. (2013)

Bottom Line: miRNAs have been shown to play essential regulatory roles in the innate immune system.Studies in humans and in disease models have revealed that dysregulation of several miRNAs such as miR-146a and miR-155 in rheumatic diseases leads to aberrant production of and/or signaling by inflammatory cytokines and, thus, critically contributes to disease pathogenesis.In addition, the recent description of the role of certain extracellular miRNAs as innate immune agonist to induce inflammatory response would have direct relevance to rheumatic diseases.

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ABSTRACT
miRNAs have been shown to play essential regulatory roles in the innate immune system. They function at multiple levels to shape the innate immune response and maintain homeostasis by direct suppression of the expression of their target proteins, preferentially crucial signaling components and transcription factors. Studies in humans and in disease models have revealed that dysregulation of several miRNAs such as miR-146a and miR-155 in rheumatic diseases leads to aberrant production of and/or signaling by inflammatory cytokines and, thus, critically contributes to disease pathogenesis. In addition, the recent description of the role of certain extracellular miRNAs as innate immune agonist to induce inflammatory response would have direct relevance to rheumatic diseases.

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Schematic presentation of select miRNAs that regulate toll-like receptor signaling pathways. During innate immune response, toll-like receptors (TLRs) are activated by various pathogens and initiate signaling transduction to induce the production of type I interferons (IFNs) and other inflammatory cytokines. miRNAs exert pronounced control of the pathway activation at multiple levels to ensure the generation of proper immune response. The miRNAs preferentially target the common signaling components and transcription factors, but also directly act on receptors and cytokine mRNAs. In most cases, decreases in the concentrations of miRNA target proteins achieve effective negative regulation and therefore avoid detrimental immune activation. However, if the target protein itself is a negative regulator (IL-1 receptor-associated kinase (IRAK)-M, suppressor of cytokine signaling-1 (SOCS1), SH2 domain-containing inositol phosphatase-1 (SHIP1)), miRNA-mediated regulation will facilitate TLR signaling and the production of inflammatory cytokines. ERK, extracellular signal-regulated kinase; IFR, interferon regulatory factor; IKK, I-kappa-B kinase; MAL, MyD88 adapter-like; MAPK, mitogen-activated protein kinase; TAB, TAK1-binding protein; TAK, transforming growth factor-beta activated kinase; TBK, TANK-binding kinase; TRAM, TRIF-related adapter molecule; TRAF, TNF receptor-associated factor; TRIF, TIR domain containing adaptor inducing IFNβ.
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Figure 1: Schematic presentation of select miRNAs that regulate toll-like receptor signaling pathways. During innate immune response, toll-like receptors (TLRs) are activated by various pathogens and initiate signaling transduction to induce the production of type I interferons (IFNs) and other inflammatory cytokines. miRNAs exert pronounced control of the pathway activation at multiple levels to ensure the generation of proper immune response. The miRNAs preferentially target the common signaling components and transcription factors, but also directly act on receptors and cytokine mRNAs. In most cases, decreases in the concentrations of miRNA target proteins achieve effective negative regulation and therefore avoid detrimental immune activation. However, if the target protein itself is a negative regulator (IL-1 receptor-associated kinase (IRAK)-M, suppressor of cytokine signaling-1 (SOCS1), SH2 domain-containing inositol phosphatase-1 (SHIP1)), miRNA-mediated regulation will facilitate TLR signaling and the production of inflammatory cytokines. ERK, extracellular signal-regulated kinase; IFR, interferon regulatory factor; IKK, I-kappa-B kinase; MAL, MyD88 adapter-like; MAPK, mitogen-activated protein kinase; TAB, TAK1-binding protein; TAK, transforming growth factor-beta activated kinase; TBK, TANK-binding kinase; TRAM, TRIF-related adapter molecule; TRAF, TNF receptor-associated factor; TRIF, TIR domain containing adaptor inducing IFNβ.

Mentions: miRNAs have also been shown to directly target mRNAs encoding individual TLRs [72]. TLR4 expression is thus inhibited by let-7e in macrophages [53], whereas TLR2 is targeted by miR-19a/b [73]. The miRNA-mediated regulation of TLR signaling pathways is summarized in Figure 1.


microRNA-mediated regulation of innate immune response in rheumatic diseases.

Luo X, Ranade K, Talker R, Jallal B, Shen N, Yao Y - Arthritis Res. Ther. (2013)

Schematic presentation of select miRNAs that regulate toll-like receptor signaling pathways. During innate immune response, toll-like receptors (TLRs) are activated by various pathogens and initiate signaling transduction to induce the production of type I interferons (IFNs) and other inflammatory cytokines. miRNAs exert pronounced control of the pathway activation at multiple levels to ensure the generation of proper immune response. The miRNAs preferentially target the common signaling components and transcription factors, but also directly act on receptors and cytokine mRNAs. In most cases, decreases in the concentrations of miRNA target proteins achieve effective negative regulation and therefore avoid detrimental immune activation. However, if the target protein itself is a negative regulator (IL-1 receptor-associated kinase (IRAK)-M, suppressor of cytokine signaling-1 (SOCS1), SH2 domain-containing inositol phosphatase-1 (SHIP1)), miRNA-mediated regulation will facilitate TLR signaling and the production of inflammatory cytokines. ERK, extracellular signal-regulated kinase; IFR, interferon regulatory factor; IKK, I-kappa-B kinase; MAL, MyD88 adapter-like; MAPK, mitogen-activated protein kinase; TAB, TAK1-binding protein; TAK, transforming growth factor-beta activated kinase; TBK, TANK-binding kinase; TRAM, TRIF-related adapter molecule; TRAF, TNF receptor-associated factor; TRIF, TIR domain containing adaptor inducing IFNβ.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3672773&req=5

Figure 1: Schematic presentation of select miRNAs that regulate toll-like receptor signaling pathways. During innate immune response, toll-like receptors (TLRs) are activated by various pathogens and initiate signaling transduction to induce the production of type I interferons (IFNs) and other inflammatory cytokines. miRNAs exert pronounced control of the pathway activation at multiple levels to ensure the generation of proper immune response. The miRNAs preferentially target the common signaling components and transcription factors, but also directly act on receptors and cytokine mRNAs. In most cases, decreases in the concentrations of miRNA target proteins achieve effective negative regulation and therefore avoid detrimental immune activation. However, if the target protein itself is a negative regulator (IL-1 receptor-associated kinase (IRAK)-M, suppressor of cytokine signaling-1 (SOCS1), SH2 domain-containing inositol phosphatase-1 (SHIP1)), miRNA-mediated regulation will facilitate TLR signaling and the production of inflammatory cytokines. ERK, extracellular signal-regulated kinase; IFR, interferon regulatory factor; IKK, I-kappa-B kinase; MAL, MyD88 adapter-like; MAPK, mitogen-activated protein kinase; TAB, TAK1-binding protein; TAK, transforming growth factor-beta activated kinase; TBK, TANK-binding kinase; TRAM, TRIF-related adapter molecule; TRAF, TNF receptor-associated factor; TRIF, TIR domain containing adaptor inducing IFNβ.
Mentions: miRNAs have also been shown to directly target mRNAs encoding individual TLRs [72]. TLR4 expression is thus inhibited by let-7e in macrophages [53], whereas TLR2 is targeted by miR-19a/b [73]. The miRNA-mediated regulation of TLR signaling pathways is summarized in Figure 1.

Bottom Line: miRNAs have been shown to play essential regulatory roles in the innate immune system.Studies in humans and in disease models have revealed that dysregulation of several miRNAs such as miR-146a and miR-155 in rheumatic diseases leads to aberrant production of and/or signaling by inflammatory cytokines and, thus, critically contributes to disease pathogenesis.In addition, the recent description of the role of certain extracellular miRNAs as innate immune agonist to induce inflammatory response would have direct relevance to rheumatic diseases.

View Article: PubMed Central - HTML - PubMed

ABSTRACT
miRNAs have been shown to play essential regulatory roles in the innate immune system. They function at multiple levels to shape the innate immune response and maintain homeostasis by direct suppression of the expression of their target proteins, preferentially crucial signaling components and transcription factors. Studies in humans and in disease models have revealed that dysregulation of several miRNAs such as miR-146a and miR-155 in rheumatic diseases leads to aberrant production of and/or signaling by inflammatory cytokines and, thus, critically contributes to disease pathogenesis. In addition, the recent description of the role of certain extracellular miRNAs as innate immune agonist to induce inflammatory response would have direct relevance to rheumatic diseases.

Show MeSH
Related in: MedlinePlus