Peter Christoph, Waibel Michaela, Radu Caius G, Yang Li V, Witte Owen N, Schulze-Osthoff Klaus, Wesselborg Sebastian, Lauber Kirsten
Department of Internal Medicine I, University of Tuebingen, 72076 Tuebingen, Germany.
J Biol Chem. 2008 Feb 29;283(9):5296-305. doi: 10.1074/jbc.M706586200. Epub 2007 Dec 18.
Phagocytosis of apoptotic cells is fundamentally important throughout life, because non-cleared cells become secondarily necrotic and release intracellular contents, thus instigating inflammatory and autoimmune responses. Secreted "find-me" and exposed "eat-me" signals displayed by the dying cell in concert with the phagocyte receptors comprise the phagocytic synapse of apoptotic cell clearance. In this scenario, lysophospholipids (lysoPLs) are assumed to act as find-me signals for the attraction of phagocytes. However, both the identity of the lyso-PLs released from apoptotic cells and the nature of the phagocyte receptor are largely unknown. By a detailed analysis of the structural requirements we show here that lysophosphatidylcholine (lysoPC), but none of the lysoPC metabolites or other lysoPLs, represents the essential apoptotic attraction signal able to trigger a phagocyte chemotactic response. Furthermore, using RNA interference and expression studies, we demonstrate that the G-protein-coupled receptor G2A, unlike its relative GPR4, is involved in the chemotaxis of monocytic cells. Thus, our study identifies lysoPC and G2A as the crucial receptor/ligand system for the attraction of phagocytes to apoptotic cells and the prevention of autoimmunity.
凋亡细胞的吞噬作用在整个生命过程中至关重要，因为未被清除的细胞会继发坏死并释放细胞内物质，从而引发炎症和自身免疫反应。垂死细胞分泌的“找到我”信号和暴露的“吃掉我”信号与吞噬细胞受体协同作用，构成了凋亡细胞清除的吞噬突触。在这种情况下，溶血磷脂（lysoPLs）被认为作为吸引吞噬细胞的“找到我”信号。然而，从凋亡细胞释放的溶血磷脂的身份以及吞噬细胞受体的性质在很大程度上尚不清楚。通过对结构要求的详细分析，我们在此表明溶血磷脂酰胆碱（lysoPC），而非lysoPC的代谢产物或其他lysoPLs，代表了能够触发吞噬细胞趋化反应的关键凋亡吸引信号。此外，通过RNA干扰和表达研究，我们证明G蛋白偶联受体G2A，与其相关受体GPR4不同，参与单核细胞的趋化作用。因此，我们的研究确定lysoPC和G2A是吞噬细胞吸引到凋亡细胞并预防自身免疫的关键受体/配体系统。
