Mucopolysaccharidosis IIIA is a neuronopathic lysosomal storage disease, characterised by heparan sulphate and other substrates accumulating in the brain. Patients develop behavioural disturbances and cognitive decline, a possible consequence of neuroinflammation and abnormal substrate accumulation. Interleukin (IL)-1β and interleukin-1 receptor antagonist (IL-1Ra) expression were significantly increased in both murine models and human MPSIII patients. We identified pathogenic mechanisms of inflammasome activation, including that disease-specific 2-O-sulphated heparan sulphate was essential for priming an IL-1β response via the Toll-like receptor 4 complex. However, mucopolysaccharidosis IIIA primary and secondary storage substrates, such as amyloid beta, were both required to activate the NLRP3 inflammasome and initiate IL-1β secretion. IL-1 blockade in mucopolysaccharidosis IIIA mice using IL-1 receptor type 1 knockout or haematopoietic stem cell gene therapy over-expressing IL-1Ra reduced gliosis and completely prevented behavioural phenotypes. In conclusion, we demonstrate that IL-1 drives neuroinflammation, behavioural abnormality and cognitive decline in mucopolysaccharidosis IIIA, highlighting haematopoietic stem cell gene therapy treatment with IL-1Ra as a potential neuronopathic lysosomal disease treatment.

中文翻译：

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用 IL-1Ra 进行造血干细胞基因治疗可挽救黏多糖贮积症 IIIA 患者的认知丧失。

粘多糖贮积症 IIIA 是一种神经元性溶酶体贮积症，其特征是硫酸乙酰肝素和其他底物在大脑中积聚。患者出现行为障碍和认知能力下降，这可能是神经炎症和异常底物积累的结果。在小鼠模型和人类 MPSIII 患者中，白细胞介素 (IL)-1β 和白细胞介素-1 受体拮抗剂 (IL-1Ra) 的表达均显着增加。我们确定了炎症小体激活的致病机制，包括疾病特异性 2-O-硫酸乙酰肝素对于通过 Toll 样受体 4 复合物引发 IL-1β 反应至关重要。然而，黏多糖贮积症 IIIA 初级和次级储存底物，如β淀粉样蛋白，都需要激活 NLRP3 炎性体并启动 IL-1β 分泌。使用 IL-1 受体 1 型敲除或造血干细胞基因治疗过度表达 IL-1Ra 对粘多糖贮积症 IIIA 小鼠进行 IL-1 阻断可减少神经胶质增生并完全阻止行为表型。总之，我们证明了 IL-1 驱动了黏多糖贮积症 IIIA 的神经炎症、行为异常和认知能力下降，突出了 IL-1Ra 造血干细胞基因治疗作为潜在的神经元性溶酶体疾病治疗。