AUTHOR=Radka Christopher D. , Frank Matthew W. , Simmons Tyler S. , Johnson Cydney N. , Rosch Jason W. , Rock Charles O. 

TITLE=Staphylococcus aureus oleate hydratase produces ligands that activate host PPARα

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=14

YEAR=2024

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2024.1352810

DOI=10.3389/fcimb.2024.1352810

ISSN=2235-2988

ABSTRACT=<p>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 <italic>Staphylococcus aureus</italic> also expresses an oleate hydratase and 10-hydroxyoctadecanoic acid (<italic>h</italic>18:0) is the most abundant oleate hydratase metabolite found at Staphylococcal skin infection sites. Here, we show <italic>h</italic>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 <italic>h</italic>18:0 selectively activates PPARα. Radiolabeling experiments with bone marrow-derived macrophages show [1-<sup>14</sup>C]<italic>h</italic>18:0 is not incorporated into cellular lipids, but is degraded by β-oxidation, and mass spectrometry detected shortened fragments of <italic>h</italic>18:0 released into the media. The catabolism of <italic>h</italic>18:0 was &gt;10-fold lower in bone marrow-derived macrophages isolated from <italic>Ppara</italic><sup>−/−</sup> knockout mice, and we recover 74-fold fewer <italic>S. aureus</italic> cells from the skin infection site of <italic>Ppara</italic><sup>−/−</sup> 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 <italic>S. aureus</italic>.</p>