Abdalla_2022_Br.J.Pharmacol__

BACKGROUND AND PURPOSE: Epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids (EpFA) are lipid mediators that are rapidly inactivated by soluble epoxide hydrolase. Uncontrolled and chronic inflammatory disorders fail to sufficiently activate endogenous regulatory pathways, including the production of specialized pro-resolving mediators (SPMs). Here, we addressed the relationship between SPMs and the EET/sEH axis and explored the impact of sEH inhibition on resolving macrophage phenotype. EXPERIMENTAL APPROACH: Mice were treated with an sEH inhibitor, EETs, or sEH inhibitor + EETs (combination) before ligature placement to induce experimental periodontitis. Using RT-qPCR, gingival samples were used to examine SPM receptors and osteolytic and inflammatory biomarkers. Maxillary alveolar bone loss was quantified by microCT and methylene blue stain. Salivary metabololipidomics were carried out to analyze SPM levels. Gingival macrophage phenotype plasticity was determined by RT-qPCR and Flow Cytometry. Bone marrow-derived macrophages were isolated to investigate the impact of sEH inhibition on macrophage polarization and SPM production. KEY RESULTS: We report that pharmacological inhibition of sEH suppresses bone resorption and the inflammatory cytokine storm in experimental periodontitis. Lipidomic analysis revealed that sEH inhibition augments levels of LXA4, RvE1, RvE2, and 4-HDoHE, concomitant with up-regulation of LTB4R1, CMKLR1/ChemR23, and ALX/FPR2 SPM receptors. Notably, there is an impact on gingival macrophage plasticity favoring an inflammation resolving phenotype with sEH inhibition. In bone marrow-derived macrophages (BMDMs), sEH inhibition reduces inflammatory macrophage activation, and resolving macrophages are triggered to produce SPMs. CONCLUSION AND IMPLICATIONS: Pharmacological sEH inhibition positively impacts SPM synthesis associated with resolving macrophages, suggesting a potential target to control osteolytic inflammatory disorders.