The ketone body acetoacetate activates human neutrophils through FFA2R

Neutrophils express many surface receptors that sense environmental changes. One such sensor is FFA2R (free fatty acid receptor 2), a receptor that detects gut microbiota-derived short chain fatty acids. As such, FFA2R has been regarded as a molecular link between metabolism and inflammation. Our recent studies on FFA2R, using its endogenous agonist propionate in combination with allosteric modulators, have identified several novel aspects of FFA2R regulation. A recent study has also identified the ketone body acetoacetate as an endogenous ligand for mouse FFA2R. Whether human FFA2R also recognizes acetoacetate and how this recognition modulates human neutrophil functions has not been earlier investigated. In this study, we found that acetoacetate can induce a decrease of cAMP and translocation of β-arrestin in cells overexpressing FFAR2. In addition, we show that similar to propionate, FFA2R specific allosteric modulators enhance acetoacetate-induced transient rise in cytosolic calcium, production of reactive oxygen species and cell migration in human neutrophils. In summary, we demonstrate that human neutrophils recognize the ketone body acetoacetate through FFA2R. Thus, our data further highlight the key role of FFA2R in inflammation and metabolism.