CR3 and Dectin-1 Collaborate in Macrophage Cytokine Response through Association on Lipid Rafts and Activation of Syk-JNK-AP-1 Pathway.
CR3 and Dectin-1 Collaborate in Macrophage Cytokine Response through Association on Lipid Rafts and Activation of Syk-JNK-AP-1 Pathway.
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DOI：
10.1371/journal.ppat.1004985
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发表时间：
2015-07
期刊：
影响因子：
6.7
通讯作者：
Wu-Hsieh BA
中科院分区：
文献类型：
--
作者：
Huang JH;Lin CY;Wu SY;Chen WY;Chu CL;Brown GD;Chuu CP;Wu-Hsieh BA
异质模式识别受体（PRR）之间的协作导致免疫反应的协同协调对于宿主对抗入侵病原体非常重要。尽管补体受体3（CR 3）和Dectin-1是检测真菌的主要PRR，但在抗真菌免疫中这两种受体之间的串扰在很大程度上是不确定的。在这里，我们利用已知与CR 3和Dectin-1以及特异性颗粒配体相互作用的荚膜组织胞浆菌来研究CR 3和Dectin-1在巨噬细胞细胞因子应答中的协作。通过采用Micro-Western阵列（MWA）、遗传方法和药理学抑制剂，我们证明了CR 3和Dectin-1通过Syk激酶的信号整合协同作用以触发巨噬细胞TNF和IL-6应答，从而允许随后增强Syk-JNK-AP-1通路的活化。在接合时，CR 3和Dectin-1在脂筏微结构域上共定位并形成簇，所述脂筏微结构域作为促进它们在信号传导活化和细胞因子产生中的合作的平台。此外，体内研究表明，CR 3和Dectin-1协同参与宿主对播散性组织胞浆菌病的防御，并指导适应性免疫应答。总之，我们的研究结果定义了CR 3和Dectin-1之间受体串扰的机制，并证明了它们在宿主防御真菌感染中的合作的重要性。在过去的几十年中，危及生命的真菌感染的发病率正在增加。深入了解真菌病原体与宿主细胞之间的相互作用对于开发抗真菌感染的新治疗策略具有重要意义。二形真菌荚膜组织胞浆菌成为传播和威胁免疫功能低下的个人的生命。这种真菌病原体利用补体受体3（CR 3）和Dectin-1（先天免疫细胞表面上的两种模式识别受体）来诱导巨噬细胞细胞因子应答。在这项研究中，我们证明了CR 3和Dectin-1通过依赖于Syk-JNK-AP-1信号传导轴激活的机制协同诱导巨噬细胞TNF和IL-6应答。CR 3和Dectin-1在H.荚膜，导致其在Syk激酶的信号传导会聚的激活和随后的细胞因子应答的诱导。此外，我们发现CR 3和Dectin-1协同指导适应性抗真菌免疫以防御H.荚膜感染我们的研究结果定义了CR 3和Dectin-1之间受体串扰的分子机制，并为宿主-真菌相互作用背景下的受体协作提供了一个有价值的模型。
Collaboration between heterogeneous pattern recognition receptors (PRRs) leading to synergistic coordination of immune response is important for the host to fight against invading pathogens. Although complement receptor 3 (CR3) and Dectin-1 are major PRRs to detect fungi, crosstalk between these two receptors in antifungal immunity is largely undefined. Here we took advantage of Histoplasma capsulatum which is known to interact with both CR3 and Dectin-1 and specific particulate ligands to study the collaboration of CR3 and Dectin-1 in macrophage cytokine response. By employing Micro-Western Array (MWA), genetic approach, and pharmacological inhibitors, we demonstrated that CR3 and Dectin-1 act collaboratively to trigger macrophage TNF and IL-6 response through signaling integration at Syk kinase, allowing subsequent enhanced activation of Syk-JNK-AP-1 pathway. Upon engagement, CR3 and Dectin-1 colocalize and form clusters on lipid raft microdomains which serve as a platform facilitating their cooperation in signaling activation and cytokine production. Furthermore, in vivo studies showed that CR3 and Dectin-1 cooperatively participate in host defense against disseminated histoplasmosis and instruct adaptive immune response. Taken together, our findings define the mechanism of receptor crosstalk between CR3 and Dectin-1 and demonstrate the importance of their collaboration in host defense against fungal infection. The incidence of life-threatening fungal infections is increasing during the last decades. A better understanding of the interactions between fungal pathogen and its host cell is important to the development of new therapeutic strategies against fungal infections. Dimorphic fungus Histoplasma capsulatum becomes disseminated and threatens life in immunocompromised individuals. This fungal pathogen utilizes complement receptor 3 (CR3) and Dectin-1, two pattern recognition receptors on the surface of innate immune cells, to induce macrophage cytokine response. In this study, we demonstrated that CR3 and Dectin-1 act collaboratively to induce macrophage TNF and IL-6 response through a mechanism dependent on activation of the Syk-JNK-AP-1 signaling axis. CR3 and Dectin-1 are recruited and form clusters on lipid raft microdomains upon stimulation by H. capsulatum, leading to activation of their signaling convergence at Syk kinase and induction of subsequent cytokine response. In addition, we showed that CR3 and Dectin-1 cooperatively instruct the adaptive antifungal immunity to defense against H. capsulatum infection. Our findings define the molecular mechanisms underlying receptor crosstalk between CR3 and Dectin-1 and provide a valuable model for receptor collaboration in the context of host-fungus interactions.
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DOI：
10.1084/jem.20021890
发表时间：
2003-05-05
期刊：
The Journal of experimental medicine
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