Oxysterol-mediated modulation of intestinal inflammation: insights into sex differences and GPR183 signaling

Oxysterols, oxidized derivatives of cholesterol, play complex roles in inflammatory processes, but their specific functions in inflammatory bowel diseases remain incompletely understood. This study investigates the roles of key oxysterols - 7α,25-dihydroxycholesterol, 25-hydroxycholesterol, 25-hydroxycholesterol-3-sulfate, and 4β-hydroxycholesterol - and potential sex differences in intestinal inflammation.

We used complementary approaches including dextran sulfate sodium-induced colitis, and ex vivo studies with colon explants, organoids, and immune cells to examine oxysterol properties. Principal component analysis was employed to analyze variance between disease and sex. In vivo administration of 7α,25-dihydroxycholesterol and NIBR189, an antagonist of its receptor GPR183, was performed to assess effects on inflammatory markers and immune cell trafficking.

We observed sex-specific differences in both basal and colitis-induced oxysterol profiles, with female mice showing greater resistance to dextran sulfate sodium-induced inflammation and distinct patterns of oxysterol metabolism. Principal component analysis highlighted a separation of samples by both treatment and sex, with dextran sulfate sodium treatment accounting for approximately 55% of variance and sex differences explaining 25%. In vitro, 25-hydroxycholesterol-3-sulfate and 7α,25-dihydroxycholesterol decreased inflammatory cytokine expression in colon explants from female mice and reduced cytokine production in THP-1-derived macrophages in a dose-dependent manner. GPR183 antagonists decreased cell activation, suggesting constitutive receptor activity. In vivo 7α,25-dihydroxycholesterol administration showed modest effects on inflammatory markers but significantly decreased immune cell counts in lymph nodes, consistent with altered immune cell trafficking.

Our findings reveal sex-specific regulation of inflammatory processes by oxysterols and highlight the therapeutic potential of targeting these pathways in inflammatory bowel diseases.