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

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.