对脂多糖的先天性免疫应答对于宿主防御革兰氏阴性细菌至关重要。为了应对细菌感染,在巨噬细胞表面表达的TLR4/MD-2复合物,单核细胞,树突状,和上皮细胞感知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)或由胞内细菌产生的胞质溶胶LPS被胞质溶胶蛋白酶caspase-4/11识别,并且宿主鸟苷酸结合蛋白参与NLRP3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传导级联的启动。然而,TLR4介导的信号传导和caspase-4/11诱导的焦亡在很大程度上参与了慢性和急性炎症的发病机理。细胞外和细胞内LPS受体-TLR4/MD-2复合物和caspase-4/11-分别能够直接结合LPS的脂质A基序。尽管TLR4复合物识别脂质A的结构基础已被深入研究和充分理解,LPS/脂质A与caspase-4/11相互作用的原子机制尚不清楚。在这里,我们描述了LPS诱导的TLR4和caspase-4/11介导的信号通路及其串扰,并仔细检查了多种LPS变体的脂质A基序的特定结构特征,据报道这些变体可以激活caspase-4/11或诱导caspase-4/11介导的NLRP3炎性体的激活(在体外转染LPS或在细胞内细菌感染细胞培养物后或通过LPS的外膜作为成分)。一般来说,炎性胱天蛋白酶显示与TLR4/MD-2复合物相当相似的结构要求,因此,“碱性”六酰化双磷酸化脂质A结构足以激活。然而,与TLR4/MD-2复合物的非常“窄”的特异性相比,caspase-4/11可以感知和响应更广泛的脂质A变体,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。此外,具有带正电荷的附件如磷酸乙醇胺或氨基阿拉伯糖的脂质A磷酸基团的修饰对于脂质A/LPS与炎性半胱天冬酶和相关蛋白质的相互作用可能是必不可少的。
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.