Sex differences in the central and peripheral omega 3 oxylipin response to acute systemic inflammation.

High-density lipoprotein (HDL) oxylipins regulate inflammation, and acute systemic inflammation can precipitate cognitive impairment. Females have more HDL and stronger immune responses than males, yet higher dementia risk. Little is known about sex differences in oxylipin responses to inflammatory stimuli and potential crosstalk between acute systemic inflammation and central oxylipin signaling in either sex. In this targeted lipidomics study, we used liquid chromatography with tandem mass spectrometry (LC/MS/MS) to characterize oxylipin profiles in plasma HDL and cerebrospinal fluid (CSF) of male and female rats following an intraperitoneal interleukin-1β (IL-1β)-induced inflammatory challenge to determine whether and how peripheral and central oxylipins respond to acute systemic inflammation in both sexes. We hypothesized that females mount a greater oxylipin response to IL-1β than males and that acute activation of peripheral inflammatory pathways changes central oxylipin concentrations. We found that IL-1β altered the abundance of omega (ω)6 and ω3 oxylipins in plasma HDL and CSF of both sexes. However, IL-1β reduced global concentrations of peripheral and central oxylipins in plasma HDL and CSF, respectively, in female rats only. Reduced oxylipin concentrations in IL-1β-treated females were driven by a loss of anti-inflammatory ω3 eicosapentaenoic acid (EPA)-derived dihydroxyeicosatetraenoic acids (DiHETEs) in plasma HDL and CSF. Interestingly, plasma HDL and CSF concentrations of EPA-derived DiHETEs were only correlated in IL-1β-treated rats, suggesting increased periphery-brain crosstalk during acute systemic inflammation. Overall, the sexually dimorphic responses of peripheral and central oxylipins to acute systemic inflammation provide molecular insight into sex differences in both innate immunity and neuroinflammatory responses. This study examines previously unexplored sex differences in oxylipin signaling cascade activation in the central nervous system and periphery during the acute phase response. This is the first study to assess and correlate oxylipins in plasma HDL and CSF in males and females following an acute systemic inflammatory challenge. This work showing reduced concentrations of anti-inflammatory ω3 EPA-derived DiHETEs in acutely inflamed females provides molecular insight into sex differences in immunity and inflammation-induced neurological changes.