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

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, Jochen Utikal, Viktor Umansky and Guoliang Cui ()
Additional contact information
Marvin Hering: German Cancer Research Center (DKFZ)
Alaa Madi: German Cancer Research Center (DKFZ)
Roger Sandhoff: German Cancer Research Center (DKFZ)
Sicong Ma: German Cancer Research Center (DKFZ)
Jingxia Wu: German Cancer Research Center (DKFZ)
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)
Diana Stichling: German Cancer Research Center (DKFZ)
Gernot Poschet: Heidelberg University
Felix Bestvater: German Cancer Research Center (DKFZ)
Larissa Frank: Heidelberg University
Jochen Utikal: German Cancer Research Center (DKFZ)
Viktor Umansky: German Cancer Research Center (DKFZ)
Guoliang Cui: German Cancer Research Center (DKFZ)

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50341-w

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