Department of Internal Medicine 3 and Institute for Clinical Immunology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
Immunity. 2012 May 25;36(5):834-46. doi: 10.1016/j.immuni.2012.03.010. Epub 2012 Apr 12.
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 (resMΦ), which blocked uptake of ACs into freshly recruited inflammatory Ly6C(hi) monocytes in a 12/15-LO-dependent manner. ResMΦ 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.
清除凋亡细胞 (ACs) 而不引发炎症对于维持自身耐受至关重要。在这里，我们报告了一种酶 12/15-脂氧合酶 (12/15-LO) 作为中央因素的作用，它控制着 AC 被分类为不同激活的单核细胞亚群。在炎症期间，AC 的摄取仅限于表达 12/15-LO 的、替代激活的驻留巨噬细胞 (resMΦ) 群体，该群体以 12/15-LO 依赖的方式阻止 AC 被新招募的炎症性 Ly6C(hi)单核细胞摄取。resMΦ 在其质膜上暴露 12/15-LO 衍生的磷脂酰乙醇胺 (oxPE) 的氧化产物，从而为 AC 的独特可溶性受体（如乳脂肪球 EGF 因子 8）生成一个吸收点，这些受体对于将 AC 摄取到炎症性单核细胞中是必需的。反过来，12/15-LO 活性的丧失导致炎症性单核细胞对 AC 的异常吞噬、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。我们的数据揭示了酶促脂质氧化在维持自身耐受过程中的一个意外关键作用。
