Novel Reporter Mouse Reveals Constitutive and Inflammatory Expression of IFN-β In Vivo

Lienenklaus, Stefan; Cornitescu, Marius; Zie̜tara, Natalia; Łyszkiewicz, Marcin; Gekara, Nelson O.; Jabłońska, Jadwiga; Edenhofer, Frank; Rajewsky, Klaus; Bruder, Dunja; Hafner, Martin; Staeheli, Peter; Weiß, Siegfried

doi:10.4049/jimmunol.0804277

Cited by 203 publications

(263 citation statements)

References 35 publications

(51 reference statements)

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“…To monitor induction of IFN-β in more detail, we also used mast cells and macrophages matured from bone marrows of the Δβ-luc mice (23). Consistently, L. monocytogenes and S. typhimurium elicited IFN-β responses in macrophages but not in mast cells (Fig.…”

Section: Ifn-β Impairs Mast Cell-dependent Mobilization Of Neutrophilmentioning

confidence: 99%

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Mast cells elicit proinflammatory but not type I interferon responses upon activation of TLRs by bacteria

Dietrich¹,

Rohde

Geffers³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Balanced induction of proinflammatory and type I IFN responses upon activation of Toll-like receptors (TLRs) determines the outcome of microbial infections and the pathogenesis of autoimmune and other inflammatory diseases. Mast cells, key components of the innate immune system, are known for their debilitating role in allergy and autoimmunity. However, their role in antimicrobial host defenses is being acknowledged increasingly. How mast cells interact with microbes and the nature of responses triggered thereby is not well characterized. Here we show that in response to TLR activation by Gram-positive and -negative bacteria or their components, mast cells elicit proinflammatory but not type I IFN responses. We demonstrate that in mast cells, bound bacteria and TLR ligands remain trapped at the cell surface and do not undergo internalization, a prerequisite for type I IFN induction. Such cells, however, can elicit type I IFNs in response to vesicular stomatitis virus which accesses the cytosolic retinoic acid-inducible gene I receptor. Although important for antiviral immunity, a strong I IFN response is known to contribute to pathogenesis of several bacterial pathogens such as Listeria monocytogenes . Interestingly, we observed that the mast cell-dependent neutrophil mobilization upon L. monocytogenes infection is highly impaired by IFN-β. Thus, the fact that mast cells, although endowed with the capacity to elicit type I IFNs in response to viral infection, elicit only proinflammatory responses upon bacterial infection shows that mast cells, key effector cells of the innate immune system, are well adjusted for optimal antibacterial and antiviral responses.

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Section: Ifn-β Impairs Mast Cell-dependent Mobilization Of Neutrophilmentioning

confidence: 99%

“…To determine whether mast cells contribute to IFN-β response during bacterial infection in vivo, we used the IFN-β-luciferase reporter mouse (Δβ-luc) (23). Following i.p.…”

Section: Ifn-β Impairs Mast Cell-dependent Mobilization Of Neutrophilmentioning

confidence: 99%

Mast cells elicit proinflammatory but not type I interferon responses upon activation of TLRs by bacteria

Dietrich¹,

Rohde

Geffers³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…MEFs were prepared from 13-day-old embryos of transgenic C57BL/6 knock-in mice carrying firefly luciferase (FF-Luc) cDNA instead of the IFN-b gene under the control of the endogenous IFN-b promoter (Lienenklaus et al, 2009). Bone marrow-derived pDCs were prepared from IFN-b deficient C57BL/6 mice (IFN-b 2/2 ) (Erlandsson et al, 1998) by cultivating bone marrow cells for 8 days in medium supplemented with Flt3-L (100 ng ml…”

Section: Methodsmentioning

confidence: 99%

“…MEFs were isolated from reporter mice carrying the IFN-b gene replaced by the firefly luciferase (FF-Luc) cDNA, thus allowing quantitative detection of IFN-b promoter activation. The expression of luciferase in the lysates of these cells correlates with the induction of endogenous IFN-b (Lienenklaus et al, 2009). Infection of these cells with different doses of recombinant THOV showed a strong activation of the IFN-b promoter by THOVML2 (Fig.…”

Section: Type I Ifn Induction By Thov Is Blocked By Mlmentioning

confidence: 99%

Thogoto virus ML protein is a potent inhibitor of the interferon regulatory factor-7 transcription factor

Buettner

Vogt

Martínez-Sobrido

et al. 2009

Journal of General Virology

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The tick-transmitted orthomyxovirus Thogoto virus (THOV) encodes the ML protein acting as a viral suppressor of the host interferon (IFN) system. Here, we describe that type I IFN is strongly induced in primary mouse embryo fibroblasts as well as plasmacytoid dendritic cells upon infection with a THOV mutant lacking the ML gene. However, wild-type THOV encoding ML suppresses induction of IFN by preventing the activation of members of the IFN regulatory factor (IRF) family. We found that reporter gene expression dependent on IRF3 and IRF7 was strongly inhibited by ML. Further experiments revealed that ML interacts with IRF7 and prevents dimerization of the transcription factor and its association with the coactivator TRAF6. Interestingly, another IRF7 activation step, nuclear translocation, is not affected by ML. Our data elucidate ML protein as a virulence factor with an IRF-specific IFN-antagonistic spectrum. INTRODUCTIONThogoto virus (THOV) is a tick-transmitted orthomyxovirus with a genome consisting of six single-stranded RNA segments that encode seven structural proteins (Hagmaier et al., 2004;Nuttall et al., 1995;van Regenmortel et al., 2000). THOV is highly sensitive to the action of type I interferons (IFN), mostly mediated by the IFN-induced antiviral Mx proteins Kochs & Haller, 1999;Pavlovic et al., 1995). In order to avoid the antiviral effects of IFN, THOV developed a strategy to suppress the induction of the IFN system. We have previously shown that the ML protein, an extended version of the viral matrix (M) protein, is a viral IFN antagonist (Hagmaier et al., 2003(Hagmaier et al., , 2004. Previous work with a recombinant THOV lacking ML expression showed that ML is essential for virus growth and pathogenesis in an IFN-competent host (Pichlmair et al., 2004). Further studies demonstrated that in the presence of ML the activation and/or action of the interferon regulatory factor-3 (IRF3) is severely affected (Jennings et al., 2005). This effect depends on direct interaction of ML with the transcription factor IIB (TFIIB) (Vogt et al., 2008), suggesting that complex formation of ML with TFIIB specifically disturbs the function of certain transcription coactivators such as IRF3.Members of the IRF family of transcription factors are involved in all aspects of IFN induction and action (Haller et al., 2006;Mamane et al., 1999;Randall & Goodbourn, 2008;Taniguchi & Takaoka, 2002). IRF3 is constitutively expressed in most cells and is essential for the induction of IFN-b as an early response to virus infection (Lin et al., 1998; Yoneyama et al., 1998) or to Toll-like receptor (TLR) agonists like dsRNA or lipopolysaccharide that bind to TLR3 and TLR4, respectively (Pitha, 2004). A positive feedback loop then leads to the induction of IRF7, which upon activation by virus infection leads to the amplification of the IFN signal mainly by transcriptional activation of the IFN-a genes in addition to IFN-b (Marie et al., 1998;Sato et al., 1998).Two independent signal transduction pathways lead to the activation of ...

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“…Recently, a reporter mouse which expresses green fluorescent protein in place of IFN-␣6 was used to demonstrate that alveolar macrophages contribute to IFN synthesis in the lungs of Newcastle disease virus (NDV)-infected animals (8). To visualize IFN synthesis in various cell types of the brain during infection with La Crosse bunyavirus (3), we had employed a different reporter mouse in which the IFN-␤-coding region was replaced by firefly luciferase (9). These studies clearly showed that virus-encoded IFN-antagonistic factors may display their activities in particular cell types of infected organs but, at the same time, may fail to inhibit IFN synthesis by immune cells (3,8).…”

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confidence: 99%

Visualizing the Beta Interferon Response in Mice during Infection with Influenza A Viruses Expressing or Lacking Nonstructural Protein 1

Kallfass

Lienenklaus

Staeheli

2013

J Virol

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bThe innate host defense against influenza virus is largely dependent on the type I interferon (IFN) system. However, surprisingly little is known about the cellular source of IFN in the infected lung. To clarify this question, we employed a reporter mouse that contains the firefly luciferase gene in place of the IFN-␤-coding region. IFN-␤-producing cells were identified either by simultaneous immunostaining of lungs for luciferase and cellular markers or by generating conditional reporter mice that express luciferase exclusively in defined cell types. Two different strains of influenza A virus were employed that either do or do not code for nonstructural protein 1 (NS1), which strongly suppresses innate immune responses of infected cells. We found that epithelial cells and lung macrophages, which represent the prime host cells for influenza viruses, showed vigorous IFN-␤ responses which, however, were severely reduced and delayed if the infecting virus was able to produce NS1. Interestingly, CD11c؉ cell populations that were either expressing or lacking macrophage markers produced the bulk of IFN-␤ at 48 h after infection with wildtype influenza A virus. Our results demonstrate that the virus-encoded IFN-antagonistic factor NS1 disarms specifically epithelial cells and lung macrophages, which otherwise would serve as main mediators of the early response against infection by influenza virus.

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Novel Reporter Mouse Reveals Constitutive and Inflammatory Expression of IFN-β In Vivo

Cited by 203 publications

References 35 publications

Mast cells elicit proinflammatory but not type I interferon responses upon activation of TLRs by bacteria

Mast cells elicit proinflammatory but not type I interferon responses upon activation of TLRs by bacteria

Thogoto virus ML protein is a potent inhibitor of the interferon regulatory factor-7 transcription factor

Visualizing the Beta Interferon Response in Mice during Infection with Influenza A Viruses Expressing or Lacking Nonstructural Protein 1

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