Absence of SHIP-1 Results in Constitutive Phosphorylation of Tank-Binding Kinase 1 and Enhanced TLR3-Dependent IFN-β Production

Gabhann, Joan Ní; Higgs, Rowan; Brennan, Kiva; Thomas, Warren; Damen, Jacqueline E.; Larbi, Nadia Ben; Krystal, Gerald; Jefferies, Caroline A.

doi:10.4049/jimmunol.0902589

Cited by 76 publications

(67 citation statements)

References 50 publications

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“…This results in hydrolyzation of the phosphatidylinositol 3-kinase (PI3K)-generated second-messenger PI-3,4,5-P3 (PIP3) to PI-3,4-P2 (38). In mice, SHIP1 has been shown to be a negative regulator of IFN-␤ production and lipopolysaccharide (LPS)-induced antibacterial response (39,40). Hence, we hypothesized that during JEV infection, SHIP1 is involved in mediating miR-155-induced IFN-␤ signaling.…”

Section: Discussionmentioning

confidence: 99%

“…Further, TBK-1 plays an essential role in TLR-and RIG-I-mediated induction of IFN-␣/␤ and host antiviral responses by regulating activation of NF-B and IRFs (47)(48)(49). In addition, SHIP1 negatively regulates IFN-␤ expression by targeting TBK-1 (40). To further correlate induction of miR-155 with regulation of SHIP1, IRFs, and NF-B activation during JEV infection, we evaluated the in vitro and in vivo effects of inhibiting miR-155 on expression of phosphorylated and total IRF3/7, TBK-1, and phosphorylated NF-B.…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA 155 Regulates Japanese Encephalitis Virus-Induced Inflammatory Response by Targeting Src Homology 2-Containing Inositol Phosphatase 1

Thounaojam

Kundu

Kaushik

et al. 2014

J Virol

114

130

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MicroRNAs (miRNAs) are single-stranded small RNA molecules that regulate various cellular processes. miRNA 155 (miR-155) regulates various aspects of innate and adaptive immune responses and plays a key role in various viral infections and the resulting neuroinflammation. The present study evaluated the involvement of miR-155 in modulating Japanese encephalitis virus (JEV)-induced neuroinflammation. We observed that miR-155 expression was upregulated during JEV infection of mouse primary microglia, the BV-2 microglia cell line, and in both mouse and human brains. In vitro and in vivo knockdown of miR-155 minimized JEV-induced inflammatory responses. In the present study, we confirmed targeting of the Src homology 2-containing inositol phosphatase 1 (SHIP1) 3= untranslated region (UTR) by miR-155 in the context of JEV infection. Inhibition of SHIP1 by miR-155 resulted in higher beta interferon (IFN-␤) and proinflammatory cytokine production through activation of TANKbinding kinase 1 (TBK-1). Based on these observations, we conclude that miR-155 modulates the neuroinflammatory response during JEV infection via negative regulation of SHIP1 expression. Thus, modulation of miR-155 could be a novel strategy to regulate JEV-induced neuroinflammation. IMPORTANCE Japanese encephalitis virus (JEV), a member of the family Flaviviridae that causes Japanese encephalitis (JE), is the most common mosquito-borne encephalitis virus in the Japanese encephalitis virus (JEV), a member of the family Flaviviridae, is a single-stranded, positive-sense RNA virus that causes Japanese encephalitis (JE) (1, 2). JE is endemic in most Southeast Asian countries (3, 4). The availability of an effective vaccine and an active immunization program have resulted in a reduced number of JE cases in a few countries (5). The early clinical features of JE include fever, headache, and vomiting. Two weeks after JEV infection, patients develop neurological symptoms, like seizure, tremor, photophobia, and movement disorder (6). These clinical features are not exclusive to JEV infection, and hence, laboratory diagnosis is needed to differentiate it from other neurological disorders. Detection of anti-JEV IgM antibodies in the cerebrospinal fluid (CSF) and serum is frequently used to diagnose JE (7). The fatality rate of JEV infection is ϳ25%. A majority of survivors (ϳ50%) have neuropsychiatric sequelae; only ϳ25% recover completely (8). Hence, JEV poses major health concerns and economic burdens in the Asia-Pacific region. During the last decade, we and others have made significant progress in the understanding molecular mechanisms involved in JEV infection.MicroRNAs (miRNAs) are small, noncoding RNAs ϳ19 to 22 nucleotides in length that regulate various cellular processes by binding to the 3= untranslated region (UTR) of target proteins, resulting in either degradation of RNA or translational suppression (9, 10). Our knowledge of the role of miRNAs in various diseases is expanding rapidly. Various reports support the role of miRNAs in neuroviral...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

MicroRNA 155 Regulates Japanese Encephalitis Virus-Induced Inflammatory Response by Targeting Src Homology 2-Containing Inositol Phosphatase 1

Thounaojam

Kundu

Kaushik

et al. 2014

J Virol

114

130

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“…To this end, a number of molecules that curtail TLRmediated IFN-b induction have been identified, including TAG, Ro52/TRIM21, and SHIP-1 (13)(14)(15). Regarding the TLR adaptor molecules themselves, until quite recently, the physiological role of these adaptors was considered to be facilitation of TLR activation and concomitant perpetuation of the signaling cascade.…”

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confidence: 99%

Absence of MyD88 Results in Enhanced TLR3-Dependent Phosphorylation of IRF3 and Increased IFN-β and RANTES Production

Siednienko

Gajanayake

Fitzgerald

et al. 2011

The Journal of Immunology

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Toll-like receptors are a group of pattern-recognition receptors that play a crucial role in “danger” recognition and induction of the innate immune response against bacterial and viral infections. TLR3 has emerged as a key sensor of viral dsRNA, resulting in the induction of the anti-viral molecule, IFN-β. Thus, a clearer understanding of the biological processes that modulate TLR3 signaling is essential. Previous studies have shown that the TLR adaptor, Mal/TIRAP, an activator of TLR4, inhibits TLR3-mediated IFN-β induction through a mechanism involving IRF7. In this study, we sought to investigate whether the TLR adaptor, MyD88, an activator of all TLRs except TLR3, has the ability to modulate TLR3 signaling. Although MyD88 does not significantly affect TLR3 ligand-induced TNF-α induction, MyD88 negatively regulates TLR3-, but not TLR4-, mediated IFN-β and RANTES production; this process is mechanistically distinct from that employed by Mal/TIRAP. We show that MyD88 inhibits IKKε-, but not TBK1-, induced activation of IRF3. In doing so, MyD88 curtails TLR3 ligand-induced IFN-β induction. The present study shows that while MyD88 activates all TLRs except TLR3, MyD88 also functions as a negative regulator of TLR3. Thus, MyD88 is essential in restricting TLR3 signaling, thereby protecting the host from unwanted immunopathologies associated with the excessive production of IFN-β. Our study offers a new role for MyD88 in restricting TLR3 signaling through a hitherto unknown mechanism whereby MyD88 specifically impairs IKKε-mediated induction of IRF3 and concomitant IFN-β and RANTES production.

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“…Further investigation revealed that SHP-2 actually interacts with TBK1 and blocks its kinase activity, thus attenuating signalling to IRF3 [107]. Another molecule, the inositol 5' phosphatase (SHIP-1), also interacts with TBK1, negatively regulating production of IFN following TLR3 stimulation [108].…”

Section: Modulation Of Signalling Downstream Of Trifmentioning

confidence: 99%

TLR3 Sensing of Viral Infection~!2009-10-01~!2010-03-30~!2010-04-28~!

Dunlevy¹,

McElvaney²,

Greene³

2010

TOIDJ

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Viral infection is detected by the innate immune system which mounts a rapid semi-selective defence involving inflammation and production of type 1 interferons. Several sensors, both cell surface and intracellular, exist to detect different types of viral motifs. Double-stranded RNA viruses and dsRNA replication intermediates are detected by tolllike receptor 3 (TLR3) as well as by retinoid-inducible gene 1 (RIG-I) like receptors. Binding of dsRNA or its synthetic analogue poly I:C to TLR3 recruits the adaptor protein TRIF and stimulates distinct pathways leading to activation of interferon regulatory factor (IRF) and NF-B. Here, we review the signalling cascades initiated by TLR3 and the modulation of these pathways.

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Absence of SHIP-1 Results in Constitutive Phosphorylation of Tank-Binding Kinase 1 and Enhanced TLR3-Dependent IFN-β Production

Cited by 76 publications

References 50 publications

MicroRNA 155 Regulates Japanese Encephalitis Virus-Induced Inflammatory Response by Targeting Src Homology 2-Containing Inositol Phosphatase 1

MicroRNA 155 Regulates Japanese Encephalitis Virus-Induced Inflammatory Response by Targeting Src Homology 2-Containing Inositol Phosphatase 1

Absence of MyD88 Results in Enhanced TLR3-Dependent Phosphorylation of IRF3 and Increased IFN-β and RANTES Production

TLR3 Sensing of Viral Infection~!2009-10-01~!2010-03-30~!2010-04-28~!

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