%0 Generic
%A Hering, Marvin
%C Heidelberg
%D 2024
%F heidok:33897
%K Zellmetabolismus, Signalübertragung, Zytokinsekretion
%R 10.11588/heidok.00033897
%T Sptlc2-derived sphinganine is indispensable for inflammatory TLR4 signaling in macrophages
%U https://archiv.ub.uni-heidelberg.de/volltextserver/33897/
%X Macrophages are key players in initiating, regulating, and driving inflammation, which, depending on the intensity and duration, can be extremely helpful or harmful during immune responses. A major pathway in macrophages driving inflammatory signaling is mediated through activation of the pattern recognition receptor Toll-like receptor (TLR) 4. After recognizing its ligand, lipopolysaccharide (LPS), TLR4 recruits adaptor proteins to the cell membrane, thereby initiating downstream signal transduction and triggering inflammation. Whether this recruitment is dependent solely on protein-protein interactions between TLR4 and adaptor proteins is unknown. Bioactive sphingolipids are regulators of multiple (patho-) physiological processes and have been associated with inflammatory macrophage signaling, with the underlying mechanisms remaining uncertain.  Here, I report that the sphingolipid sphinganine physically interacted with the adaptor proteins MyD88, TIRAP, and Tollip and promoted the recruitment of MyD88 to the cell membrane. LPS induced the expression and activity of Sptlc2, which is the key enzyme of sphingolipid metabolism, catalyzing sphinganine production and subsequent sphingolipid biosynthesis. Myeloid cell-specific deficiency in Sptlc2 was found to decrease the membrane recruitment of MyD88 and to inhibit LPS-induced M1-like macrophage growth, marker expression, metabolic activity, and cytokine production. Overexpression of membrane-anchored MyD88 in Sptlc2-deficient macrophages restored cell growth, M1-like macrophage marker expression, and inflammatory cytokine production. In an LPS-induced sepsis mouse model, Sptlc2 was upregulated in macrophages, while Sptlc2 deficiency attenuated inflammation and ameliorated symptoms of sepsis. In a melanoma mouse model in which LPS was detectable in the tumor microenvironment, Sptlc2 was upregulated in tumor macrophages, and Sptlc2 deficiency decreased anti-tumor myeloid cell responses and increased tumor growth. Therefore, sphinganine biosynthesis is required for the initiation of TLR4 signal transduction and serves as a checkpoint involved in pattern recognition by macrophages. In summary, this work sheds new light on the multifaceted role of sphingolipids as signaling molecules and underlines the huge potential of sphingolipid modulation to treat disease-associated inflammation.