12/15-Lipoxygenase Orchestrates the Clearance of Apoptotic Cells and Maintains Immunologic Tolerance
12/15-Lipoxygenase Orchestrates the Clearance of Apoptotic Cells and Maintains Immunologic Tolerance
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DOI：
10.1016/j.immuni.2012.03.010
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发表时间：
2012-05-25
期刊：
影响因子：
32.4
通讯作者：
Kroenke, Gerhard
中科院分区：
文献类型：
--
作者：
Uderhardt, Stefan;Herrmann, Martin;Kroenke, Gerhard
凋亡细胞（AC）的非炎症清除对于维持自身耐受至关重要。在这里，我们已经报道了酶12/15-脂氧合酶（12/15-LO）作为一个中心因素，管理分类的AC差异活化单核细胞亚群的作用。在炎症过程中，AC的摄取仅限于表达12/15-LO的替代活化的驻留巨噬细胞（resM Phi）群体，其以12/15-LO依赖性方式阻断AC摄取到新鲜募集的炎性Ly 6C（hi）单核细胞中。ResM Phi.暴露12/15-LO衍生的磷脂酰乙醇胺（oxPE）的氧化产物在他们的质膜，从而产生了一个水槽的不同可溶性受体的AC，如乳脂球-EGF因子8，这是必不可少的摄取AC进入炎症单核细胞。12/15-LO活性的丧失反过来导致炎性单核细胞对AC的异常吞噬作用，随后的AC衍生抗原的抗原呈递，以及狼疮样自身免疫性疾病。我们的数据揭示了一个意想不到的关键作用酶的脂质氧化过程中的自我耐受性的维护。
Noninflammatory clearance of apoptotic cells (ACs) is crucial to maintain self-tolerance. Here, we have reported a role for the enzyme 12/15-lipoxygenase (12/15-LO) as a central factor governing the sorting of ACs into differentially activated monocyte subpopulations. During inflammation, uptake of ACs was confined to a population of 12/15-LO-expressing, alternatively activated resident macrophages (resM Phi), which blocked uptake of ACs into freshly recruited inflammatory Ly6C(hi) monocytes in a 12/15-LO-dependent manner. ResM Phi. exposed 12/15-LO-derived oxidation products of phosphatidylethanolamine (oxPE) on their plasma membranes and thereby generated a sink for distinct soluble receptors for ACs such as milk fat globule-EGF factor 8, which were essential for the uptake of ACs into inflammatory monocytes. Loss of 12/15-LO activity, in turn, resulted in an aberrant phagocytosis of ACs by inflammatory monocytes, subsequent antigen presentation of AC-derived antigens, and a lupus-like autoimmune disease. Our data reveal an unexpected key role for enzymatic lipid oxidation during the maintenance of self-tolerance.