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Sphingomyelin d18:1/14:0 drives TLR4-dependent metaflammation [SM14]

ABSTRACT: Chronic low-grade inflammation, or metaflammation, is a hallmark of common non-communicable diseases. Here we identified short chain sphingomyelins as key endogenous triggers connecting nutrient excess to innate immune activation. Using atherosclerosis as a discovery model, we performed an unbiased in vivo screen integrating thousands of systemic inflammatory and metabolic measurements using supervised machine-learning analysis and identified sphingomyelin d18:1/14:0 (SM14) as a prominent disease-associated feature. SM14 directly ligates the Toll-Like Receptor 4 (TLR4) – Myeloid Differentiation Factor 2 (MD-2) (TLR4–MD-2) complex and induced a differentiation-sensitive, pro-inflammatory signalling programme. Unlike canonical TLR4 signalling induced by lipopolysaccharide (LPS), SM14 elicited a distinct signalling cascade and failed in mounting a robust interferon response at physiological concentrations. Human intervention and disease cohorts showed that circulating SM14 is diet-responsive, increased in cardiovascular and metabolic disease, and present at concentrations sufficient to activate immune cells in vitro. These findings identify SM14 as a physiologically regulated endogenous TLR4 ligand and suggest that species-resolved lipid remodelling can sustain biased innate immune signalling in chronic inflammatory disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE325520 | GEO | 2026/09/09

REPOSITORIES: GEO

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Project description:Lipid A (a hexaacylated 1,4 bis-phosphate) is a potent immune stimulant for TLR4/MD-2. Upon lipid A ligation, the TLR4/MD-2 complex dimerizes and initiates signal transduction. Historically, studies also suggested the existence of TLR4/MD-2-independent LPS signaling. Here we define the role of TLR4 and MD-2 in LPS signaling by using genome wide expression profiling in TLR4- and MD-2-deficient macrophages after stimulations with peptidoglycan-free LPS and synthetic E.coli lipid A. Of the 1,396 genes found significantly induced or repressed by any one of the treatments in the wildtype macrophages, none was present in the TLR4- or MD-2-deficient macrophages, confirming that the TLR4/MD-2 complex is the only receptor for endotoxin, and are both absolutely required for responses to LPS. Using a molecular genetics approach, we investigated the mechanism of TLR4/MD-2 activation by combining the known crystal structure of TLR4/MD-2 with computer modeling. We used lipid IVa, a defined lipid A mimetic to model the activation of mouse TLR4/MD2. The two phosphates on lipid A were predicted to interact extensively with the two positively charged patches mouse TLR4 according to our dimeric murine TLR4/MD-2/lipid IVa model. These two patches are composed of K263, R337, and K360 (Positive Patch 1), and K367 and R434 (Positive Patch 2). When either Positive Patch was abolished by mutagenesis into Ala, the responses to LPS and lipid A were almost abrogated. Thus, ionic interactions between the two phosphates on lipid A and the two positively charged patches on murine TLR4 appear to be essential for LPS receptor activation. The gene expression profile of macrophages from C57BL/6 and MD-2-deficient mice following either 10 ng LPS /mL, 100 ng lipid A/mL or 10 nM Pam2 stimulation for 2 hours were compared to PBS-stimulated control cells . In vitro differentiated macrophages from two individual WT and MD-2-deficient mice were cultured and stimulated with agonists separately, comparing the gene expression to PBS-stimulated control cells from the same mouse. Comparisons of PBS-stimulated WT cells to PBS-stimulated MD-2-deficient cells were performed to directly compare basal gene expression in the two genotypes.

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Sphingomyelin d18:1/14:0 drives TLR4-dependent metaflammation [SM14]

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