Endocytosis of soluble immune complexes leads to their clearance by FcγRIIIB but induces neutrophil extracellular traps via FcγRIIA in vivo
Endocytosis of soluble immune complexes leads to their clearance by FcγRIIIB but induces neutrophil extracellular traps via FcγRIIA in vivo
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DOI：
10.1182/blood-2011-12-401133
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发表时间：
2012-11-22
期刊：
影响因子：
20.3
通讯作者：
Mayadas, Tanya N.
中科院分区：
文献类型：
--
作者：
Chen, Kan;Nishi, Hiroshi;Mayadas, Tanya N.
可溶性免疫复合物（IC）在自身免疫性疾病中是丰富的，但中性粒细胞对这些可溶性体液因子的反应仍不清楚。此外，独特的人Fc γ RIIA和糖磷磷脂酰肌醇（GPI）连接的Fc γ RIIIB在IC介导的炎症中的个体作用仍有争议。在此，我们利用表达这些人嗜中性粒细胞Fc γ R的小鼠和细胞系来证明在不存在其已知信号传导伴侣Fc γ RIIA和整联蛋白Mac-1的情况下，单独的Fc γ RIIIB通过GPI锚定受体和液相内吞作用所使用的机制内化可溶性IC。Fc γ RIIA也使用该途径。如活体显微镜检查所示，Fc γ RIIA而非Fc γ RIIIB介导的中性粒细胞与血管外可溶性IC的相互作用导致组织中中性粒细胞胞外陷阱（NET）的形成。出乎意料的是，在野生型小鼠中，IC诱导的NETosis不依赖于NADPH氧化酶、髓过氧化物酶或中性粒细胞弹性蛋白酶。在可溶性IC主要存在于血管内的情况下，Fc γ RIIIB介导的中性粒细胞募集需要Mac-1，并与血管内IC沉积物的清除相关。总的来说，我们的研究为Fc γ RIIIB在清除脉管系统内的可溶性IC中分配了新的作用，这可能有助于维持体内平衡，而Fc γ RIIA与组织可溶性IC的结合产生NET，这是一种与自身免疫相关的促炎过程。（血。2012;120（22）：4421-4431）
Soluble immune complexes (ICs) are abundant in autoimmune diseases, yet neutrophil responses to these soluble humoral factors remain uncharacterized. Moreover, the individual role of the uniquely human Fc gamma RIIA and glycophos-phatidylinositol (GPI)-linked Fc gamma RIIIB in IC-mediated inflammation is still debated. Here we exploited mice and cell lines expressing these human neutrophil Fc gamma Rs to demonstrate that Fc gamma RIIIB alone, in the absence of its known signaling partners Fc gamma RIIA and the integrin Mac-1, internalizes soluble ICs through a mechanism used by GPI-anchored receptors and fluid-phase endocytosis. Fc gamma RIIA also uses this pathway. As shown by intravital microscopy, Fc gamma RIIA but not Fc gamma RIIIB-mediated neutrophil interactions with extravascular soluble ICs results in the formation of neutrophil extracellular traps (NETs) in tissues. Unexpectedly, in wildtype mice, IC-induced NETosis does not rely on the NADPH oxidase, myeloperoxidase, or neutrophil elastase. In the context of soluble ICs present primarily within vessels, Fc gamma RIIIB-mediated neutrophil recruitment requires Mac-1 and is associated with the removal of intravascular IC deposits. Collectively, our studies assign a new role for Fc gamma RIIIB in the removal of soluble ICs within the vasculature that may serve to maintain homeostasis, whereas Fc gamma RIIA engagement of tissue soluble ICs generates NETs, a proinflammatory process linked to autoimmunity. (Blood. 2012;120(22):4421-4431)