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Cyclopentenone Prostaglandins and Structurally Related Oxidized Lipid Species Instigate and Share Distinct Pro- and Anti-inflammatory Pathways
Cell Reports ( IF 8.8 ) Pub Date : 2020-03-31 , DOI: 10.1016/j.celrep.2020.03.019
Jonathan Muri , Qian Feng , Helene Wolleb , Abdijapar Shamshiev , Christian Ebner , Luigi Tortola , Petr Broz , Erick M. Carreira , Manfred Kopf

Oxidized lipids play a critical role in a variety of diseases with two faces: pro- and anti-inflammatory. The molecular mechanisms of this Janus-faced activity remain largely unknown. Here, we have identified that cyclopentenone-containing prostaglandins such as 15d-PGJ2 and structurally related oxidized phospholipid species possess a dual and opposing bioactivity in inflammation, depending on their concentration. Exposure of dendritic cells (DCs)/macrophages to low concentrations of such lipids before Toll-like receptor (TLR) stimulation instigates an anti-inflammatory response mediated by nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent inhibition of nuclear factor κB (NF-κB) activation and downstream targets. By contrast, high concentrations of such lipids upon TLR activation of DCs/macrophages result in inflammatory apoptosis characterized by mitochondrial depolarization and caspase-8-mediated interleukin (IL)-1β maturation independently of Nrf2 and the classical inflammasome pathway. These results uncover unexpected pro- and anti-inflammatory activities of physiologically relevant lipid species generated by enzymatic and non-enzymatic oxidation dependent on their concentration, a phenomenon known as hormesis.



中文翻译:

环戊烯酮前列腺素和结构相关的氧化脂质物种激发并共有不同的促炎和消炎途径

氧化脂质在多种疾病中起着至关重要的作用,具有两个方面:促炎和消炎。这种面对Janus的活性的分子机制仍然未知。在这里,我们已经确定,含环戊烯酮的前列腺素(例如15d-PGJ2)和与结构相关的氧化磷脂物质在炎症中具有双重且相反的生物活性,具体取决于它们的浓度。在Toll样受体(TLR)刺激之前,将树突状细胞(DCs)/巨噬细胞暴露于低浓度的此类脂质中,从而引发由核因子红系2相关因子2(Nrf2)依赖性核因子κB抑制介导的抗炎反应。 (NF-κB)激活和下游目标。相比之下,TLR激活DC /巨噬细胞后,高浓度的此类脂质会导致炎症细胞凋亡,其特征在于线粒体去极化和caspase-8介导的白介素(IL)-1β的成熟,独立于Nrf2和经典的炎症小体途径。这些结果揭示了取决于其浓度的酶促和非酶促氧化产生的生理相关脂质种类的意想不到的促炎和抗炎活性,这种现象被称为“兴奋剂”。

更新日期:2020-03-31
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