Staphylococcus aureus oleate hydratase produces ligands that activate host PPARα.

Commensal gut bacteria use oleate hydratase to release a spectrum of hydroxylated fatty acids using host-derived unsaturated fatty acids. These compounds are thought to attenuate the immune response, but the underlying signaling mechanism(s) remain to be established. The pathogen Staphylococcus aureus also expresses an oleate hydratase and 10-hydroxyoctadecanoic acid ( h 18:0) is the most abundant oleate hydratase metabolite found at Staphylococcal skin infection sites. Here, we show h 18:0 stimulates the transcription of a set of lipid metabolism genes associated with the activation of peroxisome proliferator activated receptor (PPAR) in the RAW 264.7 macrophage cell line and mouse primary bone marrow-derived macrophages. Cell-based transcriptional reporter assays show h 18:0 selectively activates PPARα. Radiolabeling experiments with bone marrow-derived macrophages show [1- ¹⁴ C] h 18:0 is not incorporated into cellular lipids, but is degraded by β-oxidation, and mass spectrometry detected shortened fragments of h 18:0 released into the media. The catabolism of h 18:0 was >10-fold lower in bone marrow-derived macrophages isolated from Ppara ^-/- knockout mice, and we recover 74-fold fewer S. aureus cells from the skin infection site of Ppara ^-/- knockout mice compared to wildtype mice. These data identify PPARα as a target for oleate hydratase-derived hydroxy fatty acids and support the existence of an oleate hydratase-PPARα signaling axis that functions to suppress the innate immune response to S. aureus .
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
(Copyright © 2024 Radka, Frank, Simmons, Johnson, Rosch and Rock.)