Institute of Anatomy, University of Bern, Bern, Switzerland.
Institute of Pharmacology, University of Würzburg, Würzburg, Germany.
Nat Commun. 2022 Aug 26;13(1):5032. doi: 10.1038/s41467-022-32624-2.
In pneumococcal meningitis, bacterial growth in the cerebrospinal fluid results in lysis, the release of toxic factors, and subsequent neuroinflammation. Exposure of primary murine glia to Streptococcus pneumoniae lysates leads to strong proinflammatory cytokine and chemokine production, blocked by inhibition of the intracellular innate receptor Nod1. Lysates enhance dynamin-dependent endocytosis, and dynamin inhibition reduces neuroinflammation, blocking ligand internalization. Here we identify the cholesterol-dependent cytolysin pneumolysin as a pro-endocytotic factor in lysates, its elimination reduces their proinflammatory effect. Only pore-competent pneumolysin enhances endocytosis in a dynamin-, phosphatidylinositol-3-kinase- and potassium-dependent manner. Endocytic enhancement is limited to toxin-exposed parts of the membrane, the effect is rapid and pneumolysin permanently alters membrane dynamics. In a murine model of pneumococcal meningitis, mice treated with chlorpromazine, a neuroleptic with a complementary endocytosis inhibitory effect show reduced neuroinflammation. Thus, the dynamin-dependent endocytosis emerges as a factor in pneumococcal neuroinflammation, and its enhancement by a cytolysin represents a proinflammatory control mechanism.
在肺炎球菌性脑膜炎中，脑脊液中的细菌生长导致裂解、有毒因子的释放以及随后的神经炎症。原代小鼠神经胶质细胞暴露于肺炎链球菌裂解物中会导致强烈的促炎细胞因子和趋化因子产生，这可被抑制细胞内先天受体 Nod1 来阻断。裂解物增强依赖于动力蛋白的内吞作用，而动力蛋白抑制减少神经炎症，阻止配体内化。在这里，我们确定胆固醇依赖性细胞溶素肺炎球菌溶血素为裂解物中的促内吞作用因子，其消除降低了它们的促炎作用。只有功能完整的肺炎球菌溶血素以依赖于动力蛋白、磷脂酰肌醇-3-激酶和钾的方式增强内吞作用。内吞作用增强仅限于膜暴露于毒素的部分，该作用是快速的，肺炎球菌溶血素永久改变膜动力学。在肺炎球菌性脑膜炎的小鼠模型中，用氯丙嗪（一种具有互补内吞作用抑制作用的神经安定药）治疗的小鼠显示神经炎症减少。因此，动力蛋白依赖性内吞作用成为肺炎球菌性神经炎症的一个因素，其被细胞溶素增强代表了一种促炎控制机制。
