Multinucleated giant cell formation exhibits features of phagocytosis with participation of the endoplasmic reticulum
Multinucleated giant cell formation exhibits features of phagocytosis with participation of the endoplasmic reticulum
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DOI：
10.1016/j.yexmp.2005.06.008
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发表时间：
2005-10-01
影响因子：
3.6
通讯作者：
Anderson, JM
中科院分区：
文献类型：
--
作者：
McNally, AK;Anderson, JM
在慢性炎症过程中，巨噬细胞融合导致多核巨细胞的形成，其机制和生理意义尚不清楚。为了解决这个问题，我们开发了一种利用IL-4、IL-13或α-生育酚产生大的异物型巨细胞（FBGC）的人巨噬细胞融合系统。扩展我们以前证明的F-肌动蛋白和甘露糖受体（MR）活性的要求，我们发现，巨噬细胞融合表现出吞噬过程的进一步功能。IL-4诱导的FBGC形成的药理学抑制表明，空泡型ATP酶、微管、内质网（ER）和钙非依赖性磷脂酶A（2）（iPLA（2））发挥关键作用，但钙依赖性PLA（2）（cPLA（2））、分泌型PLA（2）（sPLA（2））、环氧合酶或脂氧合酶不发挥关键作用。免疫细胞化学证实巨噬细胞/FBGC中iPLA表达和不表达cPLA（2）或sPLA（2）。作为ER介导的吞噬作用的标志物，钙连接蛋白和钙调蛋白在非透化融合巨噬细胞上是可检测的，并且也集中在融合界面处，在融合界面处它们与肌动蛋白在透化巨噬细胞/FBGC中共定位。此外，ER标记物与伴刀豆球蛋白A在非透性融合巨噬细胞上的反应性共定位，表明ER可能在融合事件期间呈递MR配体。这些数据首次表明，巨噬细胞融合导致形成多核巨细胞的机制表现出多种吞噬功能，ER可能参与其中。(c)2005年爱思唯尔公司All right reserved.
Macrophage fusion leading to formation of multinucleated giant cells during chronic inflammation is poorly understood in mechanism and physiological significance. To address this, we developed a system of human macrophage fusion that utilizes IL-4, IL-13, or a-tocopherol to generate large foreign body-type giant cells (FBGC). Extending our previously demonstrated requirements for F-actin and mannose receptor (MR) activity, we find that macrophage fusion exhibits further features of a phagocytic process. Pharmacological inhibition of IL-4-induced FBGC formation indicates critical roles for vacuolar-type ATPase, microtubules, the endoplasmic reticulum (ER), and calcium-independent phospholipase A(2) (iPLA(2)), but not calcium-dependent PLA(2) (cPLA(2)), secretory PLA(2) (sPLA(2)), cyclooxygenase, or lipoxygenase. Immunocytochemistry confirms iPLA, expression and absence of cPLA(2) or sPLA(2) expression in macrophages/FBGC. As markers of ER-mediated phagocytosis, calnexin and calregulin are detectable on non-permeabilized fusing macrophages and also concentrated at fusion interfaces where they co-localize with actin in penricabilized macrophages/FBGC. Furthermore, ER markers co-localize with concanavalin A reactivity on non-permeabilized fusing macrophages, suggesting that the ER may present MR ligand during fusion events. These data demonstrate for the first time that the mechanism of macrophage fusion leading to formation of multinucleated giant cells exhibits multiple features of phagocytosis with potential participation of the ER. (c) 2005 Elsevier Inc. All right reserved.