These contradicting functions were most likely due to the relative concentration and source of S1P production.338,339 In endotoxemia models, protein expression and enzymatic activity of SphK1 were observed to be elevated and responsible for hyper-inflammatory responses observed in macrophages.340,341 Recently, S1P was suggested as a DAMP involved with regulation of NLRP3 inflammasome activation in macrophages,342 while inhibition of SphK1 was shown to protect mice from sepsis-induced mortality. This evidence concerns the gene NLRP3 and Sepsis.