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  • The single nucleotide polymorphism MAL-D96N mice provide new insights into functionality of Mal in TLR immune responses

    Author(s)
    Dowling, Jennifer K
    Tate, Michelle D
    Rosli, Sarah
    Bourke, Nollaig M
    Bitto, Natalie
    Lauterbach, Mario A
    Cheung, Shane
    Ve, Thomas
    Kobe, Bostjan
    Golenbock, Douglas
    Mansell, Ashley
    Griffith University Author(s)
    Ve, Thomas
    Kobe, Bostjan
    Year published
    2019
    Metadata
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    Abstract
    MyD88 adaptor-like (Mal) protein is the most polymorphic of the four key adaptor proteins involved in TLR signaling. TLRs play a critical role in the recognition and immune response to pathogens through activation of the prototypic inflammatory transcription factor NF-κB. The study of single nucleotide polymorphisms in TLRs, adaptors, and signaling mediators has provided key insights into the function of the corresponding genes but also into the susceptibility to infectious diseases in humans. In this study, we have analyzed the immune response of mice carrying the human Mal-D96N genetic variation that has previously been ...
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    MyD88 adaptor-like (Mal) protein is the most polymorphic of the four key adaptor proteins involved in TLR signaling. TLRs play a critical role in the recognition and immune response to pathogens through activation of the prototypic inflammatory transcription factor NF-κB. The study of single nucleotide polymorphisms in TLRs, adaptors, and signaling mediators has provided key insights into the function of the corresponding genes but also into the susceptibility to infectious diseases in humans. In this study, we have analyzed the immune response of mice carrying the human Mal-D96N genetic variation that has previously been proposed to confer protection against septic shock. We have found that Mal-D96N macrophages display reduced cytokine expression in response to TLR4 and TLR2 ligand challenge. Mal-D96N macrophages also display reduced MAPK activation, NF-κB transactivation, and delayed NF-κB nuclear translocation, presumably via delayed kinetics of Mal interaction with MyD88 following LPS stimulation. Importantly, Mal-D96N genetic variation confers a physiological protective phenotype to in vivo models of LPS-, Escherichia coli-, and influenza A virus-induced hyperinflammatory disease in a gene dosage-dependent manner. Together, these results highlight the critical role Mal plays in regulating optimal TLR-induced inflammatory signaling pathways and suggest the potential therapeutic advantages of targeting the Mal D96 signaling nexus.
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    Journal Title
    Journal of Immunology
    Volume
    202
    Issue
    8
    DOI
    https://doi.org/10.4049/jimmunol.1800501
    Subject
    Immunology
    Publication URI
    http://hdl.handle.net/10072/384601
    Collection
    • Journal articles

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