PTX3 Binds MD-2 and Promotes TRIF-Dependent Immune Protection in Aspergillosis
PTX3 Binds MD-2 and Promotes TRIF-Dependent Immune Protection in Aspergillosis
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DOI：
10.4049/jimmunol.1400814
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发表时间：
2014-09-01
影响因子：
4.4
通讯作者：
Romani, Luigina
中科院分区：
文献类型：
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作者：
Bozza, Silvia;Campo, Silvia;Romani, Luigina
长五聚蛋白3（PTX 3）调节参与对烟曲霉的先天抗性的不同效应子途径，包括补体激活或通过与Fc γ R相互作用促进吞噬作用。然而，TLR是否以及如何调节PTX 3介导抗真菌药耐药性尚不清楚。在这项研究中，我们证明了PTX 3在体外结合髓样分化蛋白2（MD-2），并通过TLR 4/MD-2介导的信号传导在体内发挥其保护性抗真菌活性。与Tlr 4（-/-）小鼠相似，Md 2（-/-）小鼠对肺曲霉病表现出高度易感性，这是一种与促炎细胞因子谱和多形核中性粒细胞抗真菌活性受损相关的表型。用PTX 3处理Md 2（-/-）小鼠未能赋予针对真菌的免疫保护，而过继转移MD-2感受态多形核嗜中性粒细胞恢复了它。从机制上讲，PTX 3调理的曲霉分生孢子与MD-2的接合激活了含有TLR 4/Toll/IL-1 R结构域的衔接子，诱导IFN-β依赖性信号通路会聚在IL-10上。因此，我们已经确定了一种新的受体机制，涉及含有TLR 4/MD-2/Toll/IL-1 R结构域的衔接子诱导IFN-β介导的信号传导，由此PTX 3在A.烟曲霉感染
The long pentraxin 3 (PTX3) modulates different effector pathways involved in innate resistance to Aspergillus fumigatus, including complement activation or promotion of phagocytosis by interacting with Fc gamma Rs. However, whether and how TLRs modulate PTX3 mediates antifungal resistance is not known. In this study, we demonstrate that PTX3 binds myeloid differentiation protein 2 (MD-2) in vitro and exerts its protective antifungal activity in vivo through TLR4/MD-2-mediated signaling. Similar to Tlr4(-/-) mice, Md2(-/-) mice displayed high susceptibility to pulmonary aspergillosis, a phenotype associated with a proinflammatory cytokine profile and impaired antifungal activity of polymorphonuclear neutrophils. Treating Md2(-/-) mice with PTX3 failed to confer immune protection against the fungus, whereas adoptive transfer of MD-2-competent polymorphonuclear neutrophils restored it. Mechanistically, engagement of MD-2 by PTX3-opsonized Aspergillus conidia activated the TLR4/Toll/IL-1R domain-containing adapter inducing IFN-beta-dependent signaling pathway converging on IL-10. Thus, we have identified a novel receptor mechanism, involving the TLR4/MD-2/Toll/IL-1R domain-containing adapter inducing IFN-beta-mediated signaling, whereby PTX3 elicits antifungal resistance with limited immunopathology in A. fumigatus infection.