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IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses

Author

Listed:
  • M. Clement

    (Cardiff University)

  • J. L. Forbester

    (Cardiff University
    Oxford University)

  • M. Marsden

    (Cardiff University)

  • P. Sabberwal

    (Cardiff University)

  • M. S. Sommerville

    (Cardiff University)

  • D. Wellington

    (Oxford University
    University of Oxford)

  • S. Dimonte

    (Cardiff University)

  • S. Clare

    (Wellcome Genome Campus)

  • K. Harcourt

    (Wellcome Genome Campus)

  • Z. Yin

    (Oxford University
    University of Oxford)

  • L. Nobre

    (University of Cambridge)

  • R. Antrobus

    (University of Cambridge)

  • B. Jin

    (Fourth Military Medical University)

  • M. Chen

    (Yale University School of Medicine)

  • S. Makvandi-Nejad

    (Oxford University)

  • J. A. Lindborg

    (Yale University School of Medicine)

  • S. M. Strittmatter

    (Yale University School of Medicine)

  • M. P. Weekes

    (University of Cambridge)

  • R. J. Stanton

    (Cardiff University)

  • T. Dong

    (Oxford University
    University of Oxford)

  • I. R. Humphreys

    (Cardiff University)

Abstract

Interferon-induced transmembrane protein 3 (IFITM3) is a restriction factor that limits viral pathogenesis and exerts poorly understood immunoregulatory functions. Here, using human and mouse models, we demonstrate that IFITM3 promotes MyD88-dependent, TLR-mediated IL-6 production following exposure to cytomegalovirus (CMV). IFITM3 also restricts IL-6 production in response to influenza and SARS-CoV-2. In dendritic cells, IFITM3 binds to the reticulon 4 isoform Nogo-B and promotes its proteasomal degradation. We reveal that Nogo-B mediates TLR-dependent pro-inflammatory cytokine production and promotes viral pathogenesis in vivo, and in the case of TLR2 responses, this process involves alteration of TLR2 cellular localization. Nogo-B deletion abrogates inflammatory cytokine responses and associated disease in virus-infected IFITM3-deficient mice. Thus, we uncover Nogo-B as a driver of viral pathogenesis and highlight an immunoregulatory pathway in which IFITM3 fine-tunes the responsiveness of myeloid cells to viral stimulation.

Suggested Citation

  • M. Clement & J. L. Forbester & M. Marsden & P. Sabberwal & M. S. Sommerville & D. Wellington & S. Dimonte & S. Clare & K. Harcourt & Z. Yin & L. Nobre & R. Antrobus & B. Jin & M. Chen & S. Makvandi-Ne, 2022. "IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32587-4
    DOI: 10.1038/s41467-022-32587-4
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    References listed on IDEAS

    as
    1. Yong-Hong Zhang & Yan Zhao & Ning Li & Yan-Chun Peng & Eleni Giannoulatou & Rong-Hua Jin & Hui-Ping Yan & Hao Wu & Jin-Hua Liu & Ning Liu & Da-Yan Wang & Yue-Long Shu & Ling-Pei Ho & Paul Kellam & And, 2013. "Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with severe influenza in Chinese individuals," Nature Communications, Nature, vol. 4(1), pages 1-6, June.
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    3. Lena Alexopoulou & Agnieszka Czopik Holt & Ruslan Medzhitov & Richard A. Flavell, 2001. "Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3," Nature, Nature, vol. 413(6857), pages 732-738, October.
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