12/15-lipoxygenase-mediated enzymatic lipid oxidation regulates DC maturation and function
12/15-lipoxygenase-mediated enzymatic lipid oxidation regulates DC maturation and function
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DOI：
10.1172/jci78490
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发表时间：
2015-05-01
影响因子：
15.9
通讯作者：
Kroenke, Gerhard
中科院分区：
文献类型：
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作者：
Rothe, Tobias;Gruber, Florian;Kroenke, Gerhard
DC 能够快速成熟，从而使它们能够启动和协调 T 细胞驱动的免疫反应。必须严格控制 DC 的成熟，以避免随机 T 细胞激活和自身免疫的发展。在这里，我们确定 12/15-脂氧合酶介导的（12/15-LO 介导的）酶促脂质氧化调节 DC 活化并微调连续 T 细胞反应。具体来说，12/15-LO 活性通过产生磷脂氧化产物来确定 DC 激活阈值，磷脂氧化产物诱导依赖于转录因子 NRF2 的抗氧化反应。小鼠或人类 DC 中 12/15-LO 编码基因的缺失或 12/15-LO 的药理学抑制可加速成熟并改变细胞因子谱，从而有利于 Th17 细胞的分化。将缺乏 12/15-LO 的 DC 暴露于 12/15-LO 衍生的氧化磷脂中会减弱 DC 的活化和 Th17 细胞的发育。对 12/15-LO 缺陷小鼠的淋巴组织的分析证实了 DC 的成熟增强以及 Th17 细胞的分化增强。此外，缺乏 12/15-LO 的小鼠实验性自身免疫性脑脊髓炎导致 Th17 驱动的自身免疫性疾病加剧。总之，我们的数据表明 12/15-LO 控制 DC 的成熟，并暗示酶促脂质氧化在形成适应性免疫反应中。
DCs are able to undergo rapid maturation, which subsequently allows them to initiate and orchestrate T cell-driven immune responses. DC maturation must be tightly controlled in order to avoid random T cell activation and development of autoimmunity. Here, we determined that 12/15-lipoxygenase-meditated (12/15-LO-mediated) enzymatic lipid oxidation regulates DC activation and fine-tunes consecutive T cell responses. Specifically, 12/15-LO activity determined the DC activation threshold via generation of phospholipid oxidation products that induced an antioxidative response dependent on the transcription factor NRF2. Deletion of the 12/15-LO-encoding gene or pharmacologic inhibition of 12/15-LO in murine or human DCs accelerated maturation and shifted the cytokine profile, thereby favoring the differentiation of Th17 cells. Exposure of 12/15-LO-deficient DCs to 12/15-LO-derived oxidized phospholipids attenuated both DC activation and the development of Th17 cells. Analysis of lymphatic tissues from 12/15-LO-deficient mice confirmed enhanced maturation of DCs as well as an increased differentiation of Th17 cells. Moreover, experimental autoimmune encephalomyelitis in mice lacking 12/15-LO resulted in an exacerbated Th17-driven autoimmune disease. Together, our data reveal that 12/15-LO controls maturation of DCs and implicate enzymatic lipid oxidation in shaping the adaptive immune response.