The Endogenous Metabolite Sphingosine-1-Phosphate (S1P) Activates NOD1/2-Dependent Inflammation Triggered by Cellular Stress : [Preprint]

Cellular stress has been associated with inflammation, yet precise underlying mechanisms remain elusive. In this study, various unrelated stress inducers were employed to screen for sensors linking altered cellular homeostasis and inflammation. We identified the intracellular pattern recognition receptors NOD1/2, known receptors of bacterial peptidoglycans, as general stress sensors detecting perturbations of cellular homeostasis. NOD1/2 activation upon such perturbations required generation of the endogenous metabolite sphingosine-1-phosphate (S1P). Unlike peptidoglycan sensing via the LRR domain, cytosolic S1P directly bound to the NBD domain of NOD1/2, triggering NF-κB activation and inflammatory responses. S1P-NOD1/2 axis was essential for Bleomycin induced inflammation in vivo. In sum, we unveiled a hitherto unknown role of NOD1/2 in surveillance of cellular homeostasis through sensing of cytosolic metabolite S1P. We propose S1P as a novel endogenous stress-associated molecular pattern (SAMP) and NOD1/2 as molecular hubs integrating bacterial and metabolic cues.