Soluble epoxide hydrolase inhibition enhances production of specialized pro-resolving lipid mediator and promotes macrophage plasticity

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Abdalla, Henrique B. ; Alvarez, Carla ; Wu, Yu-Chiao ; Rojas, Paola ; Hammock, Bruce D. ; Maddipati, Krishna R. ; Trindade-da-Silva, Carlos Antonio ; Soares, Mariana Q. S. ; Clemente-Napimoga, Juliana T. ; Kantarci, Alpdogan ; Napimoga, Marcelo H. ; Van Dyke, Thomas E.

• Document type: Journal article
• Source: British Journal of Pharmacology; v. N/A, p. 19-pg., 2023-01-30.

Abstract

Background and PurposeEpoxyeicosatrienoic acids (EETs) and other epoxy fatty acids (EpFA) are lipid mediators that are rapidly inactivated by soluble epoxide hydrolase (sEH). 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 effects of sEH inhibition on resolving macrophage phenotype. Experimental ApproachMice were treated with a 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 micro-CT and methylene blue staining. SPM levels were analysed by salivary metabolo-lipidomics. Gingival macrophage phenotype plasticity was determined by RT-qPCR and flow cytometry. Effects of sEH inhibition on macrophage polarization and SPM production were assessed with bone marrow-derived macrophages (BMDMs). Key ResultsPharmacological inhibition of sEH suppressed bone resorption and the inflammatory cytokine storm in experimental periodontitis. Lipidomic analysis revealed that sEH inhibition augmented 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 was affected suggesting an inflammation resolving phenotype with sEH inhibition. In BMDMs, sEH inhibition reduced inflammatory macrophage activation, and resolving macrophages were triggered to produce SPMs. Conclusion and ImplicationsPharmacological sEH inhibition increased SPM synthesis associated with resolving macrophages, suggesting a potential target to control osteolytic inflammatory disorders. (AU)

• FAPESP's process: 17/22334-9 - Use of drug delivery systems for the development and application of anti-inflammatory agents with potential immunomodulatory and neuroprotective effects
• Grantee: Marcelo Henrique Napimoga
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/22645-0 - Evaluation of the impact of the soluble epoxide hydrolase inhibitor, TPPU, on production of specialized pro-resolving lipid mediators as a pharmacological approach for the treatment of inflammatory disorders
• Grantee: Henrique Ballassini Abdalla
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor