Lipopolysaccharide Recognition in the Crossroads of TLR4 and Caspase-4/11 Mediated Inflammatory Pathways.
Lipopolysaccharide Recognition in the Crossroads of TLR4 and Caspase-4/11 Mediated Inflammatory Pathways.
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DOI：
10.3389/fimmu.2020.585146
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发表时间：
2020
影响因子：
7.3
通讯作者：
Heine H
中科院分区：
文献类型：
--
作者：
Zamyatina A;Heine H
对脂多糖的天然免疫应答对于宿主防御革兰氏阴性菌是必需的。响应于细菌感染，在巨噬细胞、单核细胞、树突状细胞和上皮细胞的表面上表达的TLR 4/MD-2复合物感测皮摩尔浓度的内毒素LPS并触发各种促炎介质的产生。此外，来自细胞外细菌的LPS（其被内吞或转染到宿主细胞的胞质溶胶中）或由细胞内细菌产生的胞质LPS被胞质蛋白酶胱天蛋白酶-4/11和宿主鸟苷酸结合蛋白识别，所述宿主鸟苷酸结合蛋白参与NLRP 3炎性体的组装和活化。所有这些事件导致针对细菌根除的促炎信号级联的启动。然而，TLR 4介导的信号传导和caspase-4/11诱导的细胞凋亡在很大程度上参与了慢性和急性炎症的发病机制。LPS的细胞内外受体TLR 4/MD-2复合物和caspase-4/11均能直接与LPS的脂质A基序结合。尽管TLR 4复合物识别脂质A的结构基础已被深入研究和充分理解，但LPS/脂质A与caspase-4/11相互作用的原子机制在很大程度上是未知的。在这里，我们描述了LPS诱导的TLR 4和caspase-4/11介导的信号通路及其相互作用，并仔细研究了不同LPS变体的脂质A基序的特定结构特征，这些LPS变体已被报道激活caspase-4/11或诱导caspase-4/11介导的NLRP 3炎性体激活（在体外转染LPS时或在用细胞内细菌或通过LPS作为外膜囊泡的组分感染细胞培养物时）。通常，炎性半胱天冬酶显示与TLR 4/MD-2复合物相当相似的结构要求，使得“碱性”六酰化双磷酸化脂质A结构足以活化。然而，就连接在脂质A的二葡糖胺主链上的脂质链的数量和长度而言，与TLR 4/MD-2复合物的非常“狭窄”的特异性相比，胱天蛋白酶-4/11可以感测和响应更广泛的脂质A变体。此外，修饰脂质A磷酸基团与带正电荷的附件，如磷酸乙醇胺或氨基阿拉伯糖可能是必不可少的脂质A/LPS与炎症半胱天冬酶和相关蛋白的相互作用。
The innate immune response to lipopolysaccharide is essential for host defense against Gram-negative bacteria. In response to bacterial infection, the TLR4/MD-2 complex that is expressed on the surface of macrophages, monocytes, dendritic, and epithelial cells senses picomolar concentrations of endotoxic LPS and triggers the production of various pro-inflammatory mediators. In addition, LPS from extracellular bacteria which is either endocytosed or transfected into the cytosol of host cells or cytosolic LPS produced by intracellular bacteria is recognized by cytosolic proteases caspase-4/11 and hosts guanylate binding proteins that are involved in the assembly and activation of the NLRP3 inflammasome. All these events result in the initiation of pro-inflammatory signaling cascades directed at bacterial eradication. However, TLR4-mediated signaling and caspase-4/11-induced pyroptosis are largely involved in the pathogenesis of chronic and acute inflammation. Both extra- and intracellular LPS receptors—TLR4/MD-2 complex and caspase-4/11, respectively—are able to directly bind the lipid A motif of LPS. Whereas the structural basis of lipid A recognition by the TLR4 complex is profoundly studied and well understood, the atomic mechanism of LPS/lipid A interaction with caspase-4/11 is largely unknown. Here we describe the LPS-induced TLR4 and caspase-4/11 mediated signaling pathways and their cross-talk and scrutinize specific structural features of the lipid A motif of diverse LPS variants that have been reported to activate caspase-4/11 or to induce caspase-4/11 mediated activation of NLRP3 inflammasome (either upon transfection of LPS in vitro or upon infection of cell cultures with intracellular bacteria or by LPS as a component of the outer membrane vesicles). Generally, inflammatory caspases show rather similar structural requirements as the TLR4/MD-2 complex, so that a “basic” hexaacylated bisphosphorylated lipid A architecture is sufficient for activation. However, caspase-4/11 can sense and respond to much broader variety of lipid A variants compared to the very “narrow” specificity of TLR4/MD-2 complex as far as the number and the length of lipid chains attached at the diglucosamine backbone of lipid A is concerned. Besides, modification of the lipid A phosphate groups with positively charged appendages such as phosphoethanolamine or aminoarabinose could be essential for the interaction of lipid A/LPS with inflammatory caspases and related proteins.
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影响因子：
8.7
作者：
Broz P;Monack DM
通讯作者：
Monack DM
DOI：
10.1073/pnas.1607769113
发表时间：
2016-07-12
影响因子：
11.1
作者：
Aglietti, Robin A.;Estevez, Alberto;Dueber, Erin C.
通讯作者：
Dueber, Erin C.
影响因子：
8.4
作者：
Adanitsch, Florian;Shi, Jianjin;Zamyatina, Alla
通讯作者：
Zamyatina, Alla
影响因子：
3.4
作者：
Borio, Alessio;Holgado, Aurora;Zamyatina, Alla
通讯作者：
Zamyatina, Alla
影响因子：
32.4
作者：
Agostini, L;Martinon, F;Tschopp, J
通讯作者：
Tschopp, J