Draberova Lubica, Tumova Magda, Draber Petr
Department of Signal Transduction, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czechia.
Front Immunol. 2021 Jun 23;12:670205. doi: 10.3389/fimmu.2021.670205. eCollection 2021.
Mast cells are potent immune sensors of the tissue microenvironment. Within seconds of activation, they release various preformed biologically active products and initiate the process of synthesis of cytokines, chemokines, and other inflammatory mediators. This process is regulated at multiple levels. Besides the extensively studied IgE and IgG receptors, toll-like receptors, MRGPR, and other protein receptor signaling pathways, there is a critical activation pathway based on cholesterol-dependent, pore-forming cytolytic exotoxins produced by Gram-positive bacterial pathogens. This pathway is initiated by binding the exotoxins to the cholesterol-rich membrane, followed by their dimerization, multimerization, pre-pore formation, and pore formation. At low sublytic concentrations, the exotoxins induce mast cell activation, including degranulation, intracellular calcium concentration changes, and transcriptional activation, resulting in production of cytokines and other inflammatory mediators. Higher toxin concentrations lead to cell death. Similar activation events are observed when mast cells are exposed to sublytic concentrations of saponins or some other compounds interfering with the membrane integrity. We review the molecular mechanisms of mast cell activation by pore-forming bacterial exotoxins, and other compounds inducing cholesterol-dependent plasma membrane perturbations. We discuss the importance of these signaling pathways in innate and acquired immunity.
肥大细胞是组织微环境中强大的免疫传感器。在激活后的数秒内，它们会释放各种预先形成的生物活性产物，并启动细胞因子、趋化因子和其他炎症介质的合成过程。这个过程在多个层面受到调控。除了广泛研究的IgE和IgG受体、Toll样受体、MRGPR和其他蛋白质受体信号通路外，还存在一条基于革兰氏阳性细菌病原体产生的胆固醇依赖性成孔细胞毒素的关键激活途径。该途径始于外毒素与富含胆固醇的膜结合，随后发生二聚化、多聚化、前孔形成和孔形成。在低亚溶细胞浓度下，外毒素会诱导肥大细胞激活，包括脱颗粒、细胞内钙浓度变化和转录激活，从而导致细胞因子和其他炎症介质的产生。更高的毒素浓度会导致细胞死亡。当肥大细胞暴露于亚溶细胞浓度的皂苷或其他一些干扰膜完整性的化合物时，也会观察到类似的激活事件。我们综述了成孔细菌外毒素以及其他诱导胆固醇依赖性质膜扰动的化合物激活肥大细胞的分子机制。我们讨论了这些信号通路在先天免疫和获得性免疫中的重要性。
