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Sphinganine recruits TLR4 adaptors in macrophages and promotes inflammation in murine models of sepsis and melanoma

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  • Marvin Hering

    (German Cancer Research Center (DKFZ)
    Heidelberg University
    German Cancer Research Center (DKFZ)
    University Medical Center Mannheim (UMM), Ruprecht-Karls University of Heidelberg)

  • Alaa Madi

    (German Cancer Research Center (DKFZ))

  • Roger Sandhoff

    (German Cancer Research Center (DKFZ))

  • Sicong Ma

    (German Cancer Research Center (DKFZ)
    Hefei Comprehensive National Science Center)

  • Jingxia Wu

    (German Cancer Research Center (DKFZ)
    Hefei Comprehensive National Science Center)

  • Alessa Mieg

    (German Cancer Research Center (DKFZ))

  • Karsten Richter

    (German Cancer Research Center (DKFZ))

  • Kerstin Mohr

    (German Cancer Research Center (DKFZ))

  • Nora Knabe

    (German Cancer Research Center (DKFZ)
    Helmholtz Institute for Translational Oncology, Mainz (HI-TRON Mainz)—A Helmholtz Institute of the DKFZ)

  • Diana Stichling

    (German Cancer Research Center (DKFZ))

  • Gernot Poschet

    (Heidelberg University)

  • Felix Bestvater

    (German Cancer Research Center (DKFZ))

  • Larissa Frank

    (Heidelberg University
    German Cancer Research Center (DKFZ))

  • Jochen Utikal

    (German Cancer Research Center (DKFZ)
    University Medical Center Mannheim (UMM), Ruprecht-Karls University of Heidelberg
    DKFZ Hector Cancer Institute at the University Medical Center Mannheim)

  • Viktor Umansky

    (German Cancer Research Center (DKFZ)
    University Medical Center Mannheim (UMM), Ruprecht-Karls University of Heidelberg
    DKFZ Hector Cancer Institute at the University Medical Center Mannheim
    University of Heidelberg)

  • Guoliang Cui

    (German Cancer Research Center (DKFZ)
    Heidelberg University
    Hefei Comprehensive National Science Center
    Helmholtz Institute for Translational Oncology, Mainz (HI-TRON Mainz)—A Helmholtz Institute of the DKFZ)

Abstract

After recognizing its ligand lipopolysaccharide, Toll-like receptor 4 (TLR4) recruits adaptor proteins to the cell membrane, thereby initiating downstream signaling and triggering inflammation. Whether this recruitment of adaptor proteins is dependent solely on protein-protein interactions is unknown. Here, we report that the sphingolipid sphinganine physically interacts with the adaptor proteins MyD88 and TIRAP and promotes MyD88 recruitment in macrophages. Myeloid cell-specific deficiency in serine palmitoyltransferase long chain base subunit 2, which encodes the key enzyme catalyzing sphingolipid biosynthesis, decreases the membrane recruitment of MyD88 and inhibits inflammatory responses in in vitro bone marrow-derived macrophage and in vivo sepsis models. In a melanoma mouse model, serine palmitoyltransferase long chain base subunit 2 deficiency decreases anti-tumor myeloid cell responses and increases tumor growth. Therefore, sphinganine biosynthesis is required for the initiation of TLR4 signal transduction and serves as a checkpoint for macrophage pattern recognition in sepsis and melanoma mouse models.

Suggested Citation

  • Marvin Hering & Alaa Madi & Roger Sandhoff & Sicong Ma & Jingxia Wu & Alessa Mieg & Karsten Richter & Kerstin Mohr & Nora Knabe & Diana Stichling & Gernot Poschet & Felix Bestvater & Larissa Frank & J, 2024. "Sphinganine recruits TLR4 adaptors in macrophages and promotes inflammation in murine models of sepsis and melanoma," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50341-w
    DOI: 10.1038/s41467-024-50341-w
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    References listed on IDEAS

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