Innate immune response is a universal mechanism against invading pathogens. Toll-like receptors (TLRs), being part of a first line of defense, are responsible for detecting a variety of microorganisms. Among them TLR9, which is localized in endosomes, acts as a sensor for unmethylated CpG motifs present in bacteria, DNA viruses (e.g., HSV-1), or fungi. TLRs differ from one another by the use of accessory proteins. MyD88 adapter-like (Mal) adapter molecule is considered a positive regulator of TLR2- and TLR4-dependent pathways. It has been reported that this adapter may also negatively control signal transduction induced by TLR3 anchored in the endosome membrane. So far, the role of Mal adapter protein in the TLR9 signaling pathways has not been clarified. We show for the first time that Mal is engaged in TLR9-de­pendent expression of genes encoding IFNβ and TNFα in HSV-1-infected or CpG-C-treated macrophages and requires a noncanonical NF-κB pathway. Moreover, using inhibitor of ERK1/2 we confirmed involvement of these kinases in TLR9-dependent induction of IFNβ and TNFα. Our study points to a new role of Mal in TLR9 signaling through a hitherto unknown mechanism whereby lack of Mal specifically impairs ERK1/2-mediated induction of noncanonical NF-κB pathway and concomitant IFNβ and TNFα production.
J Innate Immun

中文翻译：

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HSV-1 / TLR9介导的IFNβ和TNFα诱导在巨噬细胞中具有Mal依赖性。

先天免疫应答是抵抗病原体入侵的普遍机制。作为第一道防线的一部分的Toll样受体（TLR）负责检测多种微生物。其中，位于内体的TLR9充当细菌，DNA病毒（例如HSV-1）或真菌中未甲基化CpG图案的传感器。TLR通过使用辅助蛋白彼此不同。MyD88适配器样（Mal）适配器分子被认为是TLR2和TLR4依赖性途径的正调节剂。据报道，该衔接子还可能负面控制由锚定在内体膜中的TLR3诱导的信号转导。到目前为止，Mal衔接蛋白在TLR9信号通路中的作用尚未阐明。我们首次显示Mal参与HSV-1感染或CpG-C治疗的巨噬细胞中TLR9依赖的编码IFNβ和TNFα的基因的表达，并且需要非规范的NF-κB途径。此外，使用ERK1 / 2抑制剂，我们证实了这些激酶参与了TLR9依赖的IFNβ和TNFα的诱导。我们的研究通过迄今未知的机制指出了Mal在TLR9信号转导中的新作用，其中缺少Mal会特别削弱ERK1 / 2介导的非规范性NF-κB途径的诱导并伴随IFNβ和TNFα的产生。
免疫学杂志