2. Academic Validation
  3. Sphinganine recruits TLR4 adaptors in macrophages and promotes inflammation in murine models of sepsis and melanoma

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

  • Nat Commun. 2024 Jul 18;15(1):6067. doi: 10.1038/s41467-024-50341-w.
Marvin Hering 1 2 3 4 5,  Alaa Madi 6,  Roger Sandhoff 7,  Sicong Ma 6 8,  Jingxia Wu 6 8,  Alessa Mieg 6,  Karsten Richter 9,  Kerstin Mohr 6,  Nora Knabe 6 10,  Diana Stichling 6,  Gernot Poschet 11,  Felix Bestvater 12,  Larissa Frank 13 14,  Jochen Utikal 15 16 17,  Viktor Umansky 15 16 17 18,  Guoliang Cui 19 20 21 22 23
Affiliations

Affiliations

  • 1 T Cell Metabolism Group (D192), German Cancer Research Center (DKFZ), Heidelberg, Germany. MarvinHering@web.de.
  • 2 Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. MarvinHering@web.de.
  • 3 Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany. MarvinHering@web.de.
  • 4 Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim (UMM), Ruprecht-Karls University of Heidelberg, Mannheim, Germany. MarvinHering@web.de.
  • 5 DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany. MarvinHering@web.de.
  • 6 T Cell Metabolism Group (D192), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 7 Lipid Pathobiochemistry Group (A411), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 8 Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, 230601, China.
  • 9 Electron Microscopy Core Facility (W230), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 10 Helmholtz Institute for Translational Oncology, Mainz (HI-TRON Mainz)-A Helmholtz Institute of the DKFZ, Mainz, Germany.
  • 11 Metabolomics Core Technology Platform, Centre for Organismal Studies (COS), Heidelberg University, Heidelberg, Germany.
  • 12 Light Microscopy Core Facility (W210), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 13 Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
  • 14 Division of Cellular Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 15 Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 16 Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim (UMM), Ruprecht-Karls University of Heidelberg, Mannheim, Germany.
  • 17 DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany.
  • 18 Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
  • 19 T Cell Metabolism Group (D192), German Cancer Research Center (DKFZ), Heidelberg, Germany. gcui@ustc.edu.cn.
  • 20 Faculty of Biosciences, Heidelberg University, Heidelberg, Germany. gcui@ustc.edu.cn.
  • 21 Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, 230601, China. gcui@ustc.edu.cn.
  • 22 Helmholtz Institute for Translational Oncology, Mainz (HI-TRON Mainz)-A Helmholtz Institute of the DKFZ, Mainz, Germany. gcui@ustc.edu.cn.
  • 23 Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. gcui@ustc.edu.cn.
PMID: 39025856 DOI: 10.1038/s41467-024-50341-w
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.

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