Broad and direct interaction between TLR and Siglec families of pattern recognition receptors and its regulation by Neu1.
Broad and direct interaction between TLR and Siglec families of pattern recognition receptors and its regulation by Neu1.
复制标题
TLR与模式识别受体家族之间的广泛而直接的相互作用及其对NEU1的调节。
作者：
Chen GY;Brown NK;Wu W;Khedri Z;Yu H;Chen X;van de Vlekkert D;D'Azzo A;Zheng P;Liu Y
病原体和组织损伤相关的分子模式都通过Toll样受体（TLR）诱导炎症，而唾液酸结合免疫球蛋白超家族凝集素受体（Siglecs）提供负调节。在这里，我们报告这些模式识别受体之间的广泛和直接的相互作用。混杂TLR结合剂是人SIGLEC-5/9和小鼠Siglec-3/E/F。小鼠Siglec-G未显示与任何测试的TLR的明显结合。相应地，Siglece缺失增强了树突状细胞对测试的所有微生物TLR配体的应答，而Siglecg缺失不影响对这些配体的应答。TLR 4激活触发Neu 1易位至细胞表面以破坏TLR 4：Siglec-E相互作用。相反，唾液酸酶抑制剂Neu 5Gc 2 en阻止TLR 4配体诱导的TLR 4：Siglec E/F相互作用的破坏。造血细胞中缺乏Neu 1或用唾液酸酶抑制剂Neu 5Gc 2 en系统治疗可保护小鼠免受内毒素血症。我们的数据提出了一种有趣的可能性，即Siglecs对TLR功能的广泛抑制和唾液酸酶介导的去抑制，其允许感染期间TLR激活的正反馈。DOI：http://dx.doi.org/10.7554/eLife.04066.001许多生物都有一个免疫系统，能够检测入侵的细菌、病毒和其他病原体，并在威胁造成持久损害之前触发针对威胁的反应。细胞使用许多不同的受体，可以检测这些病原体或它们产生的分子。在动物中，Toll样受体（或TLR）是一种识别在许多不同类型病原体中发现的模式或结构的蛋白质，称为病原体相关分子模式（或PAMP）。受损细胞释放的蛋白质也被Toll样受体识别，称为危险相关分子模式（DAMP）。当PAMP和DAMP被识别时，免疫应答被触发，但该应答必须被适当地控制。如果它出了差错，它可能会导致免疫细胞的过度激活，从而导致危及生命的疾病，其中之一被称为败血症。Siglecs是与糖分子结合的蛋白质，糖分子被发现附着在许多其他蛋白质上，并且已知会抑制免疫反应。然而，目前尚不清楚Siglecs是如何做到这一点的，以及它们是否可以直接与toll样受体相互作用。Chen等人现在表明，大多数（尽管不是全部）Siglec与TLR结合，并且删除可以与多种TLR结合的Siglec蛋白的基因可以增强免疫细胞对一系列微生物PAMP的反应。删除另一个不与任何TLR结合的Siglec基因对免疫反应没有影响。Chen等人认为，与Toll样受体相互作用的Siglec蛋白有点像一个刹车，减缓了受体的激活。然而，当免疫细胞通过TLR检测到外来分子时，一种称为Neu 1的酶从细胞内部重新定位到细胞表面，在那里它从TLR中去除糖分子。这破坏了TLR和Siglecs之间的相互作用，从而激活受体并触发针对入侵病原体或受损细胞的免疫反应。这代表了一种新发现的机制，可以调节TLR的信号传导。Chen等人还表明，一种化合物可以阻止Neu 1酶的功能，从而防止toll样受体（以及免疫细胞）过度激活。用该化合物治疗的小鼠被保护免于由细菌PAMP的存在引发的败血症。这些结果表明，Neu 1酶可能是治疗脓毒症的一个有前途的新靶点;现在需要进一步的工作来评估抑制这种酶引起的潜在副作用。DOI：http://dx.doi.org/10.7554/eLife.04066.002网站
Both pathogen- and tissue damage-associated molecular patterns induce inflammation through toll-like receptors (TLRs), while sialic acid-binding immunoglobulin superfamily lectin receptors (Siglecs) provide negative regulation. Here we report extensive and direct interactions between these pattern recognition receptors. The promiscuous TLR binders were human SIGLEC-5/9 and mouse Siglec-3/E/F. Mouse Siglec-G did not show appreciable binding to any TLRs tested. Correspondingly, Siglece deletion enhanced dendritic cell responses to all microbial TLR ligands tested, while Siglecg deletion did not affect the responses to these ligands. TLR4 activation triggers Neu1 translocation to cell surface to disrupt TLR4:Siglec-E interaction. Conversely, sialidase inhibitor Neu5Gc2en prevented TLR4 ligand-induced disruption of TLR4:Siglec E/F interactions. Absence of Neu1 in hematopoietic cells or systematic treatment with sialidase inhibitor Neu5Gc2en protected mice against endotoxemia. Our data raised an intriguing possibility of a broad repression of TLR function by Siglecs and a sialidase-mediated de-repression that allows positive feedback of TLR activation during infection. DOI: http://dx.doi.org/10.7554/eLife.04066.001 Many living things have an immune system that is able to detect invading bacteria, viruses and other pathogens and trigger a response targeted against the threat before it causes lasting damage. Cells employ a number of different receptors that can detect these pathogens or the molecules that they produce. In animals, toll-like receptors (or TLRs) are a type of protein that recognizes patterns or structures that are found in many different types of pathogen, known as pathogen-associated molecular patterns (or PAMPs). Injured cells release proteins that are also recognized by toll-like receptors and are called danger associated molecular patterns (or DAMPs). An immune response is triggered when PAMPs and DAMPs are recognized, but the response must be properly controlled. If it goes awry, it can result in an over-activation of the immune cells that can lead to life-threatening conditions, one of which is called sepsis. Siglecs are proteins that bind to a sugar molecule, which is found attached to many other proteins, and are known to inhibit the immune response. However, it remained unclear how Siglecs do this and if they can interact directly with toll-like receptors. Chen et al. now show that most (although not all) Siglecs bind to TLRs, and that deleting the gene for a Siglec protein that can bind to multiple TLRs boosted the response of the immune cells to a range of microbial PAMPs. Deleting the gene for another Siglec that did not bind to any TLRs had no effect on the immune response. Chen et al. suggest that the Siglec proteins that interact with toll-like receptors act a bit like a brake that slows down the activation of the receptors. However, when an immune cell detects a foreign molecule through a TLR, an enzyme called Neu1 is relocated from the inside of the cell to the cell's surface, where it removes the sugar molecules from the TLRs. This disrupts the interaction between the TLRs and the Siglecs, thus activating the receptors and triggering an immune response against the invading pathogen or damaged cells. This represents a newly discovered mechanism that can regulate the signaling of TLRs. Chen et al. also show that a chemical compound that stops the function of the Neu1 enzyme prevents the toll-like receptors—and hence the immune cells—from becoming overly activated. Mice treated with this compound are protected against sepsis triggered by the presence of a bacterial PAMP. These results suggest that the Neu1 enzyme may be a promising new target for treating sepsis; further work will now be required to assess the potential side effects caused by inhibiting this enzyme. DOI: http://dx.doi.org/10.7554/eLife.04066.002