4.5 Article

The ketone body acetoacetate activates human neutrophils through FFAR2

Journal

JOURNAL OF LEUKOCYTE BIOLOGY
Volume 113, Issue 6, Pages 577-587

Publisher

OXFORD UNIV PRESS
DOI: 10.1093/jleuko/qiad035

Keywords

acetoacetate; FFAR2; G-protein coupled receptor; ketone body; neutrophil

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

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