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

Autor: Abdalla HB; Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, Massachusetts, USA.; Laboratory of Neuroimmune Interface of Pain Research, Faculdade São Leopoldo Mandic, Instituto de Pesquisa São Leopoldo Mandic, Campinas, Brazil., Alvarez C; Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, Massachusetts, USA., Wu YC; Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, Massachusetts, USA.; Harvard School of Dental Medicine, Boston, Massachusetts, USA., Rojas P; Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, Massachusetts, USA., Hammock BD; Department of Entomology and UCD Comprehensive Cancer Center, University of California, Davis, California, USA., Maddipati KR; Department of Pathology, Wayne State University, Detroit, Michigan, USA., Trindade-da-Silva CA; Laboratory of Neuroimmune Interface of Pain Research, Faculdade São Leopoldo Mandic, Instituto de Pesquisa São Leopoldo Mandic, Campinas, Brazil., Soares MQS; Laboratory of Neuroimmune Interface of Pain Research, Faculdade São Leopoldo Mandic, Instituto de Pesquisa São Leopoldo Mandic, Campinas, Brazil., Clemente-Napimoga JT; Laboratory of Neuroimmune Interface of Pain Research, Faculdade São Leopoldo Mandic, Instituto de Pesquisa São Leopoldo Mandic, Campinas, Brazil., Kantarci A; Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, Massachusetts, USA., Napimoga MH; Laboratory of Neuroimmune Interface of Pain Research, Faculdade São Leopoldo Mandic, Instituto de Pesquisa São Leopoldo Mandic, Campinas, Brazil., Van Dyke TE; Department of Applied Oral Sciences, The Forsyth Institute, Cambridge, Massachusetts, USA.; Department of Oral Medicine, Infection, and Immunity, Faculty of Medicine, Harvard University, Boston, Massachusetts, USA.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2023 Jun; Vol. 180 (12), pp. 1597-1615. Date of Electronic Publication: 2023 Jan 30.
DOI: 10.1111/bph.16009
Abstrakt: Background and Purpose: Epoxyeicosatrienoic 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 Approach: Mice 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 Results: Pharmacological 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 Implications: Pharmacological sEH inhibition increased SPM synthesis associated with resolving macrophages, suggesting a potential target to control osteolytic inflammatory disorders.
(© 2022 British Pharmacological Society.)
Databáze: MEDLINE
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