可溶性环氧化物水解酶抑制增强了专门的促解决脂质介质的产生，并促进了巨噬细胞的可塑性。
Soluble epoxide hydrolase inhibition enhances production of specialized pro-resolving lipid mediator and promotes macrophage plasticity.
机构信息
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.
出版信息
Br J Pharmacol. 2023 Jun;180(12):1597-1615. doi: 10.1111/bph.16009. Epub 2023 Jan 30.
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.
背景与目的
环氧化物水解酶（sEH）可迅速使环氧脂肪酸（EpFA）和其他环氧脂肪酸失活。未受控制的慢性炎症性疾病不能充分激活内源性调节途径，包括专门的促解决介质（SPM）的产生。在这里，我们研究了 SPM 和 EET/sEH 轴之间的关系，并探讨了 sEH 抑制对解决巨噬细胞表型的影响。
实验方法
在结扎诱导实验性牙周炎之前，用 sEH 抑制剂、EETs 或 sEH 抑制剂+EETs（组合）处理小鼠。使用 RT-qPCR，用牙龈样本检测 SPM 受体和溶骨性和炎症性生物标志物。通过微 CT 和亚甲蓝染色定量上颌牙槽骨丢失。通过唾液代谢脂质组学分析 SPM 水平。通过 RT-qPCR 和流式细胞术确定牙龈巨噬细胞表型可塑性。用骨髓来源的巨噬细胞（BMDM）评估 sEH 抑制对巨噬细胞极化和 SPM 产生的影响。
主要结果
sEH 抑制抑制了实验性牙周炎中的骨吸收和炎症细胞因子风暴。脂质组学分析显示，sEH 抑制增加了 LXA4、RvE1、RvE2 和 4-HDoHE 的水平，同时上调了 LTB4R1、CMKLR1/ChemR23 和 ALX/FPR2 SPM 受体。值得注意的是，sEH 抑制对牙龈巨噬细胞可塑性有影响，提示其具有炎症缓解表型。在 BMDM 中，sEH 抑制减少了炎症性巨噬细胞的激活，并触发了具有炎症缓解表型的巨噬细胞产生 SPM。
结论和意义
药理学抑制 sEH 增加了与解决巨噬细胞相关的 SPM 合成，提示控制溶骨性炎症性疾病的潜在靶点。
Zotero 插件