Cross-talk between TLR4 and FcgammaReceptorIII (CD16) pathways.
Cross-talk between TLR4 and FcgammaReceptorIII (CD16) pathways.
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DOI：
10.1371/journal.ppat.1000464
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发表时间：
2009-06
期刊：
影响因子：
6.7
通讯作者：
Ward PA
中科院分区：
文献类型：
--
作者：
Rittirsch D;Flierl MA;Day DE;Nadeau BA;Zetoune FS;Sarma JV;Werner CM;Wanner GA;Simmen HP;Huber-Lang MS;Ward PA
Toll 样受体 (TLR) 的病原体模式识别以及免疫复合物形成后通过与 Fc 受体 (FcR) 结合而清除病原体代表了触发免疫和炎症反应的核心机制。在本研究中，在体外和体内评估了 TLR4 和 FcγR 之间的联系。最引人注目的是，基于免疫共沉淀分析，IgG 免疫复合物 (IgGIC) 体外激活吞噬细胞导致 TLR4 与 FcγRIII (CD16) 结合。根据细胞因子的产生情况，TLR4 突变 (mut) 小鼠的中性粒细胞和巨噬细胞在体外对脂多糖 (LPS) 或 IgGIC 无反应。这种现象伴随着 FcRγ 亚基的免疫受体酪氨酸激活基序 (ITAM) 内的酪氨酸残基无法磷酸化。为了将这些发现转移到体内，采用了气管内施用 LPS 或 IgGIC 诱导的两种不同的急性肺损伤 (ALI) 模型。正如预期的那样，LPS 诱导的 ALI 在 TLR4 mut 和 TLR4−/− 小鼠中被消除。出乎意料的是，TLR4 mut 和 TLR4−/− 小鼠在 IgGIC 沉积在肺部后也能抵抗 ALI 的发展。总之，我们的研究结果表明，TLR4 和 FcγRIII 通路在受体水平上在结构和功能上相连，并且 TLR4 对于通过 FcRγ 亚基激活的 FcγRIII 信号传导是不可或缺的。免疫系统传统上分为先天性免疫系统和适应性免疫系统。模式识别受体（PRR）共同识别入侵微生物的分子结构，然后启动免疫反应。 PRR 包含 Toll 样受体 (TLR) 家族，其中包括 TLR4，它对于细菌脂多糖 (LPS) 的反应至关重要。作为适应性免疫系统的一部分，免疫细胞上的 Fc 受体 (FcR) 识别抗原抗体复合物，并将抗体介导的免疫反应与细胞效应功能联系起来。在这里，我们描述了病原体识别受体 Toll 样受体 4 (TLR4) 和 IgG 免疫复合物受体 (IgGIC)、Fcγ 受体 (FcγRs) 之间的串扰。我们发现 TLR4 参与 FcγRIII (CD16) 信号传导，并且 TLR4 和 FcγRIII 的异二聚化发生在 IgGIC 而不是 LPS 存在的情况下。因此，功能失调的 TLR4 信号传导导致体外免疫细胞对 LPS 和 IgGIC 均无反应，导致气管内施用 LPS 或肺内免疫复合物沉积后不存在急性肺损伤。总之，我们描述了 TLR4 和 FcγRIII 通路在结构和功能上是相关的。这些发现为先天性免疫和适应性免疫之间的相互作用提供了新的见解，它们在受体水平和受体后信号通路上相互作用密切。
Pathogen-pattern-recognition by Toll-like receptors (TLRs) and pathogen clearance after immune complex formation via engagement with Fc receptors (FcRs) represent central mechanisms that trigger the immune and inflammatory responses. In the present study, a linkage between TLR4 and FcγR was evaluated in vitro and in vivo. Most strikingly, in vitro activation of phagocytes by IgG immune complexes (IgGIC) resulted in an association of TLR4 with FcγRIII (CD16) based on co-immunoprecipitation analyses. Neutrophils and macrophages from TLR4 mutant (mut) mice were unresponsive to either lipopolysaccharide (LPS) or IgGIC in vitro, as determined by cytokine production. This phenomenon was accompanied by the inability to phosphorylate tyrosine residues within immunoreceptor tyrosine-based activation motifs (ITAMs) of the FcRγ-subunit. To transfer these findings in vivo, two different models of acute lung injury (ALI) induced by intratracheal administration of either LPS or IgGIC were employed. As expected, LPS-induced ALI was abolished in TLR4 mut and TLR4−/− mice. Unexpectedly, TLR4 mut and TLR4−/− mice were also resistant to development of ALI following IgGIC deposition in the lungs. In conclusion, our findings suggest that TLR4 and FcγRIII pathways are structurally and functionally connected at the receptor level and that TLR4 is indispensable for FcγRIII signaling via FcRγ-subunit activation. The immune system is traditionally divided into innate and adaptive entities. Pattern-recognition receptors (PRRs) collectively recognize molecular structures of invading microorganisms, followed by initiation of immune responses. PRRs comprise the toll-like receptor (TLR) family, including TLR4, which is essential for responses to bacterial lipopolysaccharide (LPS). As part of the adaptive immune system, Fc receptors (FcRs) on immune cells recognize antigen–antibody complexes and link antibody-mediated immune responses to cellular effector functions. Here, we describe cross-talk between the pathogen-recognition-receptor toll-like receptor 4 (TLR4) and receptors for IgG immune complexes (IgGIC), Fcγ receptors (FcγRs). We found that TLR4 is involved in FcγRIII (CD16) signaling and that heterodimerization of TLR4 and FcγRIII occurs in the presence of IgGIC but not LPS. Consequently, dysfunctional TLR4 signaling results in unresponsiveness of immune cells in vitro to both LPS and IgGIC, resulting in absence of acute lung injury after intratracheal administration of LPS or intrapulmonary immune complex deposition. In summary, we describe that TLR4 and FcγRIII pathways are structurally and functionally connected. These findings provide new insights of the interplay between innate and adaptive immunity, which closely interact with each other at the receptor level and post receptor signaling pathways.
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