CD11b/CD18 (Mac-1) is a novel surface receptor for extracellular double-stranded RNA to mediate cellular inflammatory responses.
CD11b/CD18 (Mac-1) is a novel surface receptor for extracellular double-stranded RNA to mediate cellular inflammatory responses.
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DOI：
10.4049/jimmunol.1202136
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发表时间：
2013-01-01
期刊：
影响因子：
--
通讯作者：
Hong JS
中科院分区：
文献类型：
--
作者：
Zhou H;Liao J;Aloor J;Nie H;Wilson BC;Fessler MB;Gao HM;Hong JS
在病毒感染过程中，胞外dsRNA是一种有效的信号分子，可以激活包括巨噬细胞在内的许多天然免疫细胞。TLR3是已知的胞外dsRNA受体，胞外dsRNA内化是内体TLR3激活所必需的。保存的TLR3缺陷巨噬细胞对细胞外dsRNA的炎症反应强烈支持dsRNA介导的免疫反应中TLR3不依赖的机制。本研究证实CD11b/CD18(Mac-1)是一种表面整合素受体，能识别细胞外dsRNA并诱导巨噬细胞免疫反应。CD11b缺乏降低了多聚肌苷：多核糖核酸(PolyI：C，一种合成的dsRNA)在小鼠血清、肝脏和培养的腹膜巨噬细胞中诱导的炎性细胞因子。DsRNA结合实验和共聚焦免疫荧光分析表明，Mac-1，特别是CD11b亚基与巨噬细胞表面的Poly I：C相互作用并共定位。进一步的机制研究揭示了Mac-1识别dsRNA后发生的两个不同的信号事件。首先，Mac-1通过激活PI3K信号通路和增强巨噬细胞中TLR3依赖的干扰素调节因子3(IRF3)的激活，促进Poly I：C内化。其次，PolyI：C以TLR3非依赖、Mac-1依赖的方式诱导吞噬细胞NADPH氧化酶(NOX2)激活。随后，NOX2产生的胞内活性氧激活了丝裂原活化蛋白激酶和核因子κB通路。我们的结果表明，胞外dsRNA激活Mac-1以增强TLR3依赖的信号转导，并触发TLR3不依赖但依赖于Mac-1的炎性氧化信号，为巨噬细胞识别胞外dsRNA调节先天性免疫反应确定了一个新的机制基础。这项研究确定Mac-1是一种新的细胞外dsRNA表面受体，并暗示Mac-1可能成为病毒相关炎症性疾病的治疗靶点。
During viral infection, extracellular dsRNA is a potent signaling molecule that activates many innate immune cells including macrophages. TLR3 is a well-known receptor for extracellular dsRNA, and internalization of extracellular dsRNA is required for endosomal TLR3 activation. Preserved inflammatory responses of TLR3-deficient macrophages to extracellular dsRNA strongly support a TLR3-independent mechanism in dsRNA-mediated immune responses. The present study demonstrated that CD11b/CD18 (Mac-1), a surface integrin receptor, recognized extracellular dsRNA and induced macrophage immune responses. CD11b deficiency reduced inflammatory cytokine induction elicited by polyinosinic:polycytidylic acid (poly I:C, a synthetic dsRNA) in mouse sera and livers and in cultured peritoneal macrophages. DsRNA-binding assay and confocal immunofluorescence showed that Mac-1, especially the CD11b subunit, interacted and colocalized with poly I:C on the surface of macrophages. Further mechanistic studies revealed two distinct signaling events following dsRNA recognition by Mac-1. Firstly, Mac-1 facilitated poly I:C internalization through the activation of PI3K signaling and enhanced TLR3-dependent activation of interferon regulatory factor 3 (IRF3) in macrophages. Secondly, poly I:C induced activation of phagocyte NADPH oxidase (NOX2) in a TLR3-independent, but Mac-1 dependent manner. Subsequently, NOX2-derived intracellular reactive oxygen species activated MAPK and NFκB pathways. Our results indicate that extracellular dsRNA activates Mac-1 to enhance TLR3-dependent signaling and to trigger TLR3-independent, but Mac-1-dependent inflammatory oxidative signaling, identifying a novel mechanistic basis for macrophages to recognize extracellular dsRNA to regulate innate immune responses. This study identifies Mac-1 as a novel surface receptor for extracellular dsRNA and implicates Mac-1 as a potential therapeutic target for virus-related inflammatory diseases.
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