Abstract
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 (h18:0) is the most abundant oleate hydratase metabolite found at Staphylococcal skin infection sites. Here, we show h18:0 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 h18:0 selectively activates PPARa. Radiolabeling experiments with bone marrow-derived macrophages show [1- 14 C]h18:0 is not incorporated into cellular lipids, but is degraded by b- oxidation, and mass spectrometry detected shortened fragments of h18:0 released into the media. The catabolism of h18:0 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 PPARa as a target for oleate hydratase-derived hydroxy fatty acids and support the existence of an oleate hydratase-PPARa signaling axis that functions to suppress the innate immune response to S. aureus.
Document Type
Article
Publication Date
3-2024
Digital Object Identifier (DOI)
https://doi.org/10.3389/fcimb.2024.1352810
Funding Information
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by National Institutes of Health, United States grants R00AI166116 (CDR) and GM034496 (COR), and the American Lebanese Syrian Associated Charities, United States.
Repository Citation
Radka, Christopher D.; Frank, Matthew W.; Simmons, Tyler S.; Johnson, Cydney N.; Rosch, Jason W.; and Rock, Charles O., "Staphylococcus aureus oleate hydratase produces ligands that activate host PPARa" (2024). Markey Cancer Center Faculty Publications. 239.
https://uknowledge.uky.edu/markey_facpub/239
Included in
Immunology of Infectious Disease Commons, Infectious Disease Commons, Medical Microbiology Commons, Oncology Commons, Other Immunology and Infectious Disease Commons, Other Microbiology Commons
Notes/Citation Information
© 2024 Radka, Frank, Simmons, Johnson, Rosch and Rock. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.