Chronic low-grade inflammation, also called metaflammation, is associated with prevalent non-communicable diseases. Anti-inflammatory therapy provides a clinical benefit in patients, but the triggers that incite metaflammation remain largely unknown. To uncover non-genetic inflammatory factors influencing Western-diet mediated inflammation and pathology, we performed an unbiased in vivo screen measuring thousands of host- and microbe-derived molecules in a mouse model of atherosclerosis. Machine learning-supported analyses identified, next to known pro- and anti-atherogenic factors, the medium fatty acid-chain sphingomyelin d18:1/14:0 (S14) as highly positively associated with atherogenesis. S14 activated macrophage innate immune signalling, immune-metabolic reprogramming and pro-inflammatory gene transcription. The inflammatory activity of S14 was TLR4- and MD-2-dependent, consistent with biochemical and molecular dynamics simulation analyses showing that S14 promoted the formation of active TLR4/MD-2 dimers. Human interventional and observational trials demonstrated that dietary changes altered concentrations of S14 and that increased circulating S14 was associated with carotid plaque development in obese individuals. Collectively, these findings identify an inducible endogenous ligand for TLR4 that drives metaflammation, providing the rationale for preventative approaches and pharmacological interventions that may curb detrimental inflammation secondary to Western-type lifestyle habits.

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The Oxford-Berlin Partnership is an academic partnership between the University of Oxford and the Berlin University Alliance. KIR and DRFZ are embedded in this unique setting supporting a variety of possible academic activities in both Oxford & Berlin, including seed-funding, mobility calls and symposia. The possibility of submitting joint applications to third-party funders (e.g. Horizon Europe)could promote the rheumatological research at both locations.