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

Siednienko, Jakub; Gajanayake, Thusitha; Fitzgerald, Katherine A.; Moynagh, Paul N.; Miggin, Sinéad M.

doi:10.4049/jimmunol.1003093

Cited by 69 publications

(72 citation statements)

References 39 publications

(42 reference statements)

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“…It has been found that in mammals MyD88 interacts directly with several IRFs including IRF1, IRF4, IRF5, and IRF7 (28,29,33,34). An initial study has suggested that human MyD88 does not interact with IRF3 (9); however, later research demonstrated that murine MyD88 does interact with IRF3 (35). Unlike MyD88, whose amino acid sequence is relatively well conserved, the sequences of the IRFs have diverged to a much greater extent throughout the vertebrate evolution (36).…”

Section: Discussionmentioning

confidence: 99%

MyD88 Interacts with Interferon Regulatory Factor (IRF) 3 and IRF7 in Atlantic Salmon (Salmo salar)

Iliev

Sobhkhez

Fremmerlid

et al. 2011

Journal of Biological Chemistry

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Background: MyD88 directly interacts and affects IRF activation in mammals, but no information has been available about lower vertebrates. Results: Transgenic MyD88 interacts with IRF3 and IRF7A/B and modulates the IRF-induced IFN response and accumulates in aggresomes in Atlantic salmon. Conclusion: MyD88 is involved in the regulation of the IRF-induced IFN response in Atlantic salmon. Significance: The results shed light on the evolution of the innate immune response in vertebrates.

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Section: Discussionmentioning

confidence: 99%

MyD88 Interacts with Interferon Regulatory Factor (IRF) 3 and IRF7 in Atlantic Salmon (Salmo salar)

Iliev

Sobhkhez

Fremmerlid

et al. 2011

Journal of Biological Chemistry

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“…In addition, signals derived from fibroblasts such as IL-1-dependent induction of IL-6, GM-CSF, or keratinocyte growth factor (KGF) [51,52], or T-cell-dependent production of IL-22 [53] or IL-31 [54] might be indirectly involved in keratinocyte proliferation after OVA sensitization. Since MyD88 deficiency enhances TRIF-induced signaling [55], it might be possible that this would lead to enhanced IFN-b production. TRIF signaling limits skin barrier dysfunction in a model of aspergillusinduced eczema in mice [56].…”

Section: Discussionmentioning

confidence: 99%

Requirement of MyD88 signaling in keratinocytes for Langerhans cell migration and initiation of atopic dermatitis‐like symptoms in mice

et al. 2016

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Atopic dermatitis (AD) is a chronic inflammatory disease controlled by the innate and adaptive immune system. To elucidate the impact of innate immune signaling in AD, we analyzed MyD88-deficient mice in a murine model of AD-like dermatitis by epicutaneous sensitization with ovalbumin (OVA). Global MyD88 deficiency led to reduced epidermal thickening and diminished accumulation of macrophages within the inflamed skin. In addition, we observed impaired emigration of Langerhans cells (LCs) out of the epidermis of MyD88-deficient mice. These findings indicate that MyD88 deficiency affects various skin-resident cell types in the AD model. Moreover, production of IFN-g, IL-17, and CCL17 was reduced in skin draining lymph node cells and OVA-specific immunoglobulin levels were lower in MyD88-deficient mice. We further investigated the role of MyD88 in keratinocytes, as keratinocytes contribute to AD pathology. Exclusive expression of MyD88 in epidermal keratinocytes partially restored LC emigration after AD induction and expression of CCL17 in skin draining lymph nodes (LNs), but did not promote epidermal thickening nor production of IL-17. Altogether, these data demonstrate that MyD88 signaling in keratinocytes is able to restore LC migration in an otherwise MyD88-deficient background, and significantly contributes to the development of AD-like dermatitis.Keywords: Allergology r Dermatitis r Innate immunity r Langerhans cells r MyD88 signaling r Skin inflammation Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAtopic dermatitis (AD) is a chronic, inflammatory skin disease [1,2] characterized by pruritic, scaly, and erythematous skin lesions and is caused by genetic, environmental, and immunologic factors Correspondence: Dr. Heike Weighardt e-mail: Heike.weighardt@uni-bonn.de [3]. Activation of the immune system during AD results in a mixed Th1 and Th2 response, but also Th22 and Th17 subsets contribute to the immune response [4]. In the majority of AD patients the disease is associated with the development of allergen-specific IgE titers, however also a non-IgE-associated form exists [2]. * These authors contributed equally to this work.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 982Sonja Didovic et al. Eur. J. Immunol. 2016. 46: 981-992 The development of AD involves barrier defects caused by mutations in structural genes such as filaggrin or disturbed protease activity in the epidermis [5,6] and a dysregulation of the immune system of the skin [6,7]. Impaired barrier function is characterized by enhanced transepidermal water loss (TEWL), which may enhance entry of pathogens, allergens, or toxins and thereby facilitate activation of the skin immune system [6,7]. The skin dendritic cell (DC) network comprises epidermal Langerhans cells (LCs) and different subsets of dermal DCs (dDCs) [8,9]. Upon antigen acquisition both LCs and dDCs get activated and migrate to the draining lymph nodes (LNs) to induce an immune re...

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“…HEK293, HEK293-TLR3, HEK293-TLR4, and HEK293-TLR9 cells (5 3 10 4 cells/well; 96-well plate) were transfected with 80 ng/well luciferase reporter gene plasmid for NF-kB and IFN-b and cotransfected with the expression vectors encoding ADAM15, TRIF, MyD88, and MDA5, as indicated, using lipofectamine, as previously described (8). A total of 40 ng/well phRL-TK (TK-Renilla-luciferase) reporter gene was cotransfected simultaneously to normalize data for transfection efficiency.…”

Section: Reporter Gene Assaysmentioning

confidence: 99%

“…The IRF3/7 dimers then translocate to the nucleus, in association with transcriptional coactivators, such as CBP and p300, and bind to target sequences in DNA, such as IFN-stimulated response elements (8,9). Also, the IRFs, together with the transcription factors ATF-2/c-Jun and NF-kB from the IFN-b enhanceosome, bind to a nucleosome-free enhancer region within the IFN-b promoter upstream of the transcription start site, leading to transcriptional activation of the IFN-b gene (10).…”

mentioning

confidence: 99%

“…Also, the IRFs, together with the transcription factors ATF-2/c-Jun and NF-kB from the IFN-b enhanceosome, bind to a nucleosome-free enhancer region within the IFN-b promoter upstream of the transcription start site, leading to transcriptional activation of the IFN-b gene (10). The enhancer itself is divided into four positive regulatory domains (PRD) whereby NF-kB binds to the PRDII element within the IFN-b enhancer region, ATF-2/c-Jun binds to the PRDIV element and is activated by JNK, and IRF3 and IRF7 bind to the PRDI-III element (8). Also, TRIF-dependent activation of NF-kB occurs through binding of TRAF6 to TRIF and subsequent ubiquitination-dependent recruitment and activation of TAK1 (11).…”

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confidence: 99%

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TRIF-Mediated TLR3 and TLR4 Signaling Is Negatively Regulated by ADAM15

Ahmed

Maratha

Butt

et al. 2013

The Journal of Immunology

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TLRs 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. The TLR adaptor molecule, Toll/IL-1R domain-containing adaptor inducing IFN (TRIF), facilitates TLR3 and TLR4 signaling and concomitant activation of the transcription factors, NF-κB and IFN regulatory factor 3, leading to proinflammatory cytokine production. Whereas numerous studies have been undertaken toward understanding the role of TRIF in TLR signaling, little is known about the signaling components that regulate TRIF-dependent TLR signaling. To this end, TRIF-interacting partners were identified by immunoprecipitation of the TRIF signaling complex, followed by protein identification using liquid chromatography mass spectrometry. Following stimulation of cells with a TLR3 or TLR4 ligand, we identified a disintegrin and metalloprotease (ADAM)15 as a novel TRIF-interacting partner. Toward the functional characterization of the TRIF:ADAM15 interaction, we show that ADAM15 acts as a negative regulator of TRIF-mediated NF-κB and IFN-β reporter gene activity. Also, suppression of ADAM15 expression enhanced polyriboinosinic polyribocytidylic acid and LPS-mediated proinflammatory cytokine production via TRIF. In addition, suppression of ADAM15 expression enhanced rhinovirus 16 and vesicular stomatitis virus–mediated proinflammatory cytokine production. Interestingly, ADAM15 mediated the proteolytic cleavage of TRIF. Thus, ADAM15 serves to curtail TRIF-dependent TLR3 and TLR4 signaling and, in doing so, protects the host from excessive production of proinflammatory cytokines and matrix metalloproteinases. In conclusion, to our knowledge, our study clearly shows for the first time that ADAM15 plays an unexpected role in TLR signaling, acting as an anti-inflammatory molecule through impairment of TRIF-mediated TLR signaling.

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

Cited by 69 publications

References 39 publications

MyD88 Interacts with Interferon Regulatory Factor (IRF) 3 and IRF7 in Atlantic Salmon (Salmo salar)

MyD88 Interacts with Interferon Regulatory Factor (IRF) 3 and IRF7 in Atlantic Salmon (Salmo salar)

Requirement of MyD88 signaling in keratinocytes for Langerhans cell migration and initiation of atopic dermatitis‐like symptoms in mice

TRIF-Mediated TLR3 and TLR4 Signaling Is Negatively Regulated by ADAM15

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