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

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF IMMUNOLOGY; v. 212, n. 3, p. 14-pg., 2024-02-01.

Resumo

Epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids are short -acting lipids involved in resolution of inflammation. Their short half-life, due to its metabolism by soluble epoxide hydrolase (sEH), limits their effects. Specialized proresolving mediators (SPMs) are endogenous regulatory lipids insufficiently synthesized in uncontrolled and chronic inflammation. Using an experimental periodontitis model, we pharmacologically inhibited sEH, examining its impact on T cell activation and systemic SPM production. In humans, we analyzed sEH in the gingival tissue of periodontitis patients. Mice were treated with sEH inhibitor (sEHi) and/or EETs before ligature placement and treated for 14 d. Bone parameters were assessed by microcomputed tomography and methylene blue staining. Blood plasma metabololipidomics were carried out to quantify SPM levels. We also determined T cell activation by reverse transcription -quantitative PCR and flow cytometry in cervical lymph nodes. Human gingival samples were collected to analyze sEH using ELISA and electrophoresis. Data reveal that pharmacological sEHi abrogated bone resorption and preserved bone architecture. Metabololipidomics revealed that sEHi enhances lipoxin A4, lipoxin B4, resolvin E2, and resolvin D6. An increased percentage of regulatory T cells over Th17 was noted in sEHi-treated mice. Lastly, inflamed human gingival tissues presented higher levels and expression of sEH than did healthy gingivae, being positively correlated with periodontitis severity. Our findings indicate that sEHi preserves bone architecture and stimulates SPM production, associated with regulatory actions on T cells favoring resolution of inflammation. Because sEH is enhanced in human gingivae from patients with periodontitis and connected with disease severity, inhibition may prove to be an attractive target for managing osteolytic inflammatory diseases. The Journal of Immunology, 2024, 212: 433-445. (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