Staphylococcus aureus oleate hydratase produces ligands that activate host PPARα

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

Research output: Contribution to journalArticlepeer-review

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 PPARα. Radiolabeling experiments with bone marrow-derived macrophages show [1-14C]h18:0 is not incorporated into cellular lipids, but is degraded by β-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 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.

Original languageEnglish
Article number1352810
JournalFrontiers in Cellular and Infection Microbiology
Volume14
DOIs
StatePublished - 2024

Bibliographical note

Publisher Copyright:
Copyright © 2024 Radka, Frank, Simmons, Johnson, Rosch and Rock.

Keywords

  • Staphylococcus aureus
  • fatty acid oxidation (FAO)
  • host-microbe interaction
  • hydroxy fatty acid
  • macrophage
  • oleate hydratase
  • peroxisome proliferator activated receptor alpha (PPARα)
  • signaling

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Microbiology (medical)
  • Infectious Diseases

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