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CXCL4 synergizes with TLR8 for TBK1-IRF5 activation, epigenomic remodeling and inflammatory response in human monocytes

Author

Listed:
  • Chao Yang

    (Hospital for Special Surgery)

  • Mahesh Bachu

    (Hospital for Special Surgery)

  • Yong Du

    (Hospital for Special Surgery)

  • Caroline Brauner

    (Hospital for Special Surgery)

  • Ruoxi Yuan

    (Hospital for Special Surgery)

  • Marie Dominique Ah Kioon

    (Hospital for Special Surgery)

  • Giancarlo Chesi

    (Hospital for Special Surgery)

  • Franck J. Barrat

    (Hospital for Special Surgery
    Weill Cornell Medicine
    Weill Cornell Medicine)

  • Lionel B. Ivashkiv

    (Hospital for Special Surgery
    Weill Cornell Medicine
    Weill Cornell Medicine)

Abstract

Regulation of endosomal Toll-like receptor (TLR) responses by the chemokine CXCL4 is implicated in inflammatory and fibrotic diseases, with CXCL4 proposed to potentiate TLR responses by binding to nucleic acid TLR ligands and facilitating their endosomal delivery. Here we report that in human monocytes/macrophages, CXCL4 initiates signaling cascades and downstream epigenomic reprogramming that change the profile of the TLR8 response by selectively amplifying inflammatory gene transcription and interleukin (IL)−1β production, while partially attenuating the interferon response. Mechanistically, costimulation by CXCL4 and TLR8 synergistically activates TBK1 and IKKε, repurposes these kinases towards an inflammatory response via coupling with IRF5, and activates the NLRP3 inflammasome. CXCL4 signaling, in a cooperative and synergistic manner with TLR8, induces chromatin remodeling and activates de novo enhancers associated with inflammatory genes. Our findings thus identify new regulatory mechanisms of TLR responses relevant for cytokine storm, and suggest targeting the TBK1-IKKε-IRF5 axis may be beneficial in inflammatory diseases.

Suggested Citation

  • Chao Yang & Mahesh Bachu & Yong Du & Caroline Brauner & Ruoxi Yuan & Marie Dominique Ah Kioon & Giancarlo Chesi & Franck J. Barrat & Lionel B. Ivashkiv, 2022. "CXCL4 synergizes with TLR8 for TBK1-IRF5 activation, epigenomic remodeling and inflammatory response in human monocytes," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31132-7
    DOI: 10.1038/s41467-022-31132-7
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