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Uncontrolled and chronic inflammatory disorders fail to sufficiently activate endogenous regulatory pathways, including the production of specialized pro\u2010resolving 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>Mice were treated with a sEH inhibitor, EETs, or sEH inhibitor\u2009+\u2009EETs (combination) before ligature placement to induce experimental periodontitis. Using RT\u2010qPCR, gingival samples were used to examine SPM receptors and osteolytic and inflammatory biomarkers. Maxillary alveolar bone loss was quantified by micro\u2010CT and methylene blue staining. SPM levels were analysed by salivary metabolo\u2010lipidomics. Gingival macrophage phenotype plasticity was determined by RT\u2010qPCR and flow cytometry. Effects of sEH inhibition on macrophage polarization and SPM production were assessed with bone marrow\u2010derived macrophages (BMDMs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>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\u2010HDoHE, concomitant with up\u2010regulation 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>Pharmacological sEH inhibition increased SPM synthesis associated with resolving macrophages, suggesting a potential target to control osteolytic inflammatory disorders.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.16009","type":"journal-article","created":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T12:45:31Z","timestamp":1670849131000},"page":"1597-1615","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Soluble epoxide hydrolase inhibition enhances production of specialized pro\u2010resolving lipid mediator and promotes macrophage plasticity"],"prefix":"10.1111","volume":"180","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7517-2830","authenticated-orcid":false,"given":"Henrique B.","family":"Abdalla","sequence":"first","affiliation":[{"name":"Department of Applied Oral Sciences The Forsyth Institute  Cambridge Massachusetts USA"},{"name":"Laboratory of Neuroimmune Interface of Pain Research, Faculdade S\u00e3o Leopoldo Mandic Instituto de Pesquisa S\u00e3o Leopoldo Mandic  Campinas Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Alvarez","sequence":"additional","affiliation":[{"name":"Department of Applied Oral Sciences The Forsyth Institute  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu\u2010Chiao","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Applied Oral Sciences The Forsyth Institute  Cambridge Massachusetts USA"},{"name":"Harvard School of Dental Medicine  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Rojas","sequence":"additional","affiliation":[{"name":"Department of Applied Oral Sciences The Forsyth Institute  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1408-8317","authenticated-orcid":false,"given":"Bruce D.","family":"Hammock","sequence":"additional","affiliation":[{"name":"Department of Entomology and UCD Comprehensive Cancer Center University of California  Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna R.","family":"Maddipati","sequence":"additional","affiliation":[{"name":"Department of Pathology Wayne State University  Detroit Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Antonio","family":"Trindade\u2010da\u2010Silva","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroimmune Interface of Pain Research, Faculdade S\u00e3o Leopoldo Mandic Instituto de Pesquisa S\u00e3o Leopoldo Mandic  Campinas Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana Q. 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