Journal Article

DKFZ-2024-01498

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Sphinganine recruits TLR4 adaptors in macrophages and promotes inflammation in murine models of sepsis and melanoma.

Hering, M. (First author)DKFZ* ; Madi, A. A. M.DKFZ* ; Sandhoff, R.DKFZ* ; Ma, S.DKFZ* ; Wu, J.DKFZ* ; Mieg, A.DKFZ* ; Richter, K.DKFZ* ; Mohr, K.DKFZ* ; Knabe, N.DKFZ* ; Stichling, D.DKFZ* ; Poschet, G. ; Bestvater, F.DKFZ* ; Frank, L. J.DKFZ* ; Utikal, J.DKFZ* ; Umansky, V.DKFZ* ; Cui, G. (Last author)DKFZ*

2024
Nature Publishing Group UK [London]

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Please use a persistent id in citations: 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.

Keyword(s): Animals (MeSH) ; Toll-Like Receptor 4: metabolism (MeSH) ; Sepsis: metabolism (MeSH) ; Macrophages: metabolism (MeSH) ; Myeloid Differentiation Factor 88: metabolism (MeSH) ; Mice (MeSH) ; Sphingosine: analogs & derivatives (MeSH) ; Sphingosine: metabolism (MeSH) ; Melanoma: metabolism (MeSH) ; Melanoma: pathology (MeSH) ; Melanoma: genetics (MeSH) ; Serine C-Palmitoyltransferase: metabolism (MeSH) ; Serine C-Palmitoyltransferase: genetics (MeSH) ; Humans (MeSH) ; Signal Transduction (MeSH) ; Disease Models, Animal (MeSH) ; Inflammation: metabolism (MeSH) ; Receptors, Interleukin-1: metabolism (MeSH) ; Receptors, Interleukin-1: genetics (MeSH) ; Membrane Glycoproteins: metabolism (MeSH) ; Membrane Glycoproteins: genetics (MeSH) ; Mice, Inbred C57BL (MeSH) ; Mice, Knockout (MeSH) ; HEK293 Cells (MeSH) ; Lipopolysaccharides (MeSH) ; Toll-Like Receptor 4 ; Myeloid Differentiation Factor 88 ; Sphingosine ; Tlr4 protein, mouse ; Serine C-Palmitoyltransferase ; safingol ; Receptors, Interleukin-1 ; Membrane Glycoproteins ; Myd88 protein, mouse ; TIRAP protein, mouse ; TIRAP protein, human ; Lipopolysaccharides

Note: #EA:D192#EA:A370#LA:D192# / HI-TRON

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Contributing Institute(s):

1. T-Zell-Metabolismus (D192)
2. KKE Dermatoonkologie (A370)
3. Lipid-Pathobiochemie (A411)
4. Elektronenmikroskopie (W230)
5. Lichtmikroskopie (W210)
6. Zelluläre Immunologie (D110)

Research Program(s):

1. 314 - Immunologie und Krebs (POF4-314) (POF4-314)

Appears in the scientific report 2024

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