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.

• Tipo de documento: Artigo Científico
• Fonte: British Journal of Pharmacology; v. N/A, p. 19-pg., 2023-01-30.

Resumo

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)

• Processo FAPESP: 17/22334-9 - Uso de sistemas de liberação de fármacos para o desenvolvimento e aplicabilidade de agentes anti-inflamatórios com potencial efeito imunomodulador e neuroprotetor
• Beneficiário: Marcelo Henrique Napimoga
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 19/22645-0 - Avaliação do impacto do inibidor da epóxi hidrolase solúvel, TPPU, na produção de mediadores lipídicos especializados pro-resolvinas como uma abordagem farmacológica para o tratamento de desordens inflamatórias
• Beneficiário: Henrique Ballassini Abdalla
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado