SOCS3 is a modulator of human macrophage phagocytosis
SOCS3 is a modulator of human macrophage phagocytosis
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DOI：
10.1189/jlb.3a1215-554rr
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发表时间：
2016-10-01
影响因子：
5.5
通讯作者：
Wilson, Heather M.
中科院分区：
文献类型：
--
作者：
Gordon, Peter;Okai, Blessing;Wilson, Heather M.
细胞因子信号转导抑制因子（SOCS）蛋白被认为是调节巨噬细胞炎症活动的关键反馈抑制剂，但对它们是否以及如何影响吞噬作用知之甚少。在这里，我们评估了SOCS 3在驱动人类巨噬细胞对凋亡细胞的炎症表型和吞噬摄取中的作用，以及有效吞噬所必需的信号传导途径。在M1激活的人单核细胞源性巨噬细胞中，使用短干扰RNA技术进行SOCS 3沉默，导致促炎标志物的表达降低和M2巨噬细胞标志物的表达增加。引人注目的是，我们首次证明了SOCS 3敲低显著增强了M1巨噬细胞对羧酸盐修饰的珠粒和凋亡中性粒细胞的吞噬能力。使用活细胞视频显微镜，我们发现，SOCS 3敲低从根本上影响颗粒吞噬的时间动力学，使第二个目标的更快的摄取和延迟postengulfment处理，证明了吞噬体成熟标志物的延迟收购。SOCS 3敲低通过增加PI 3 K和Ras相关的C3肉毒杆菌毒素底物1（Rac 1）活性影响吞噬作用，这是吞噬和清除凋亡细胞所必需的途径。SOCS 3沉默细胞中增强的吞噬作用被药理学PI 3 K抑制逆转。此外，我们发现，肌动蛋白聚合，下游的PI 3 K/Rac 1激活，显着改变SOCS 3沉默的细胞，提供了一种机制，其更大的吞噬活性。这些发现支持了一种新的模型，SOCS 3不仅在驱动巨噬细胞炎症反应中发挥重要作用，而且还调节组织肌动蛋白细胞骨架的关键信号通路，以调节吞噬过程的效率。
Suppressor of cytokine signaling (SOCS) proteins are recognized as key feedback inhibitors modulating the inflammatory activities of macrophages, but comparatively little is known about whether and how they affect phagocytosis. Here, we evaluated the role of SOCS3 in driving the inflammatory phenotype and phagocytic uptake of apoptotic cells by human macrophages and the signaling pathways that are necessary for efficient phagocytosis. In M1-activated human monocyte-derived macrophages, SOCS3 silencing, using short interfering RNA technology, resulted in a decreased expression of proinflammatory markers and an increased expression of M2 macrophage markers. Strikingly, we demonstrated for the first time that SOCS3 knockdown significantly enhances the phagocytic capacity of M1 macrophages for carboxylate-modified beads and apoptotic neutrophils. With the use of live-cell video microscopy, we showed that SOCS3 knockdown radically affects the temporal dynamics of particle engulfment, enabling more rapid uptake of a second target and delaying postengulfment processing, as evidenced by deferred acquisition of phagosome maturation markers. SOCS3 knockdown impacts on phagocytosis through increased PI3K and Ras-related C3 botulinum toxin substrate 1 (Rac1) activity, pathways essential for engulfment and clearance of apoptotic cells. Enhanced phagocytosis in SOCS3-silenced cells was reversed by pharmacological PI3K inhibition. Furthermore, we revealed that actin polymerization, downstream of PI3K/Rac1 activation, was significantly altered in SOCS3-silenced cells, providing a mechanism for their greater phagocytic activity. The findings support a new model, whereby SOCS3 not only plays an important role in driving macrophage inflammatory responses but modulates key signaling pathways organizing the actin cytoskeleton to regulate the efficiency of phagocytic processes.