12,13-二羟基-9z-十八烯酸(12,13-DiHOME)是一种亚油酸二醇,衍生自细胞色素P-450(CYP)环氧合酶和环氧化物水解酶(EH)代谢。12,13-DiHOME与先天免疫反应中的炎症和线粒体损伤有关,但12,13-DiHOME如何促成这些影响尚不清楚。我们假设12,13-DiHOME通过影响NOD样受体蛋白3(NLRP3)炎性体激活来增强巨噬细胞炎症。为了检验这个假设,我们利用人单核细胞THP1细胞分化为巨噬细胞样细胞与佛波醇肉豆蔻酸盐乙酸(PMA)。在THP1巨噬细胞的脂多糖(LPS)引发过程中存在的12,13-DiHOME加剧了尼日利亚霉素诱导的NLRP3炎性体激活。使用高分辨率呼吸测量法,我们观察到用LPS+12,13-DiHOME引发改变线粒体呼吸功能。线粒体自噬,使用mito-Keima测量,也被引发期间存在的12,13-DiHOME调节。这些线粒体效应与LPS12,13-DiHOME引发的巨噬细胞对尼德霉素诱导的线粒体去极化和活性氧产生的敏感性增加有关。Ligericin诱导的线粒体损伤和NLRP3炎症小体激活的LPS12,13-DiHOME引发的巨噬细胞被线粒体钙单转体(MCU)抑制剂消融,鲁265.在LPS引发过程中存在的12,13-DiHOME也增强了在原代鼠骨髓来源的巨噬细胞中尼德霉素诱导的NLRP3炎性体激活。总之,这些数据表明12,13-DiHOME通过增强巨噬细胞中的NLRP3炎性体激活而具有促炎作用.
12,13-dihydroxy-9z-octadecenoic acid (12,13-DiHOME) is a linoleic acid diol derived from cytochrome P-450 (CYP) epoxygenase and epoxide hydrolase (EH) metabolism. 12,13-DiHOME is associated with inflammation and mitochondrial damage in the innate immune response, but how 12,13-DiHOME contributes to these effects is unclear. We hypothesized that 12,13-DiHOME enhances macrophage inflammation through effects on NOD-like receptor protein 3 (NLRP3) inflammasome activation. To test this hypothesis, we utilized human monocytic THP1 cells differentiated into macrophage-like cells with phorbol myristate acetate (PMA). 12,13-DiHOME present during lipopolysaccharide (LPS)-priming of THP1 macrophages exacerbated nigericin-induced NLRP3 inflammasome activation. Using high-resolution respirometry, we observed that priming with LPS+12,13-DiHOME altered mitochondrial respiratory function. Mitophagy, measured using mito-Keima, was also modulated by 12,13-DiHOME present during priming. These mitochondrial effects were associated with increased sensitivity to nigericin-induced mitochondrial depolarization and reactive oxygen species production in LPS+12,13-DiHOME-primed macrophages. Nigericin-induced mitochondrial damage and NLRP3 inflammasome activation in LPS+12,13-DiHOME-primed macrophages were ablated by the mitochondrial calcium uniporter (MCU) inhibitor, Ru265. 12,13-DiHOME present during LPS-priming also enhanced nigericin-induced NLRP3 inflammasome activation in primary murine bone marrow-derived macrophages. In summary, these data demonstrate a pro-inflammatory role for 12,13-DiHOME by enhancing NLRP3 inflammasome activation in macrophages.