Sphingomyelin d18:1/14:0 activates TLR4 in metaflammation

Abstract Chronic low-grade inflammation, also called metaflammation, is associated with prevalent non-communicable diseases, such as atherosclerosis. 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 atherosclerosis severity, 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.