Hunter syndrome or mucopolysaccharidosis type II (MPS II) is an X-linked recessive disease caused by the deficiency of iduronate 2-sulfatase (IDS), leading to storage of undegraded heparan and dermatan sulfate. Patients with the severe form present neurological abnormalities, but the mechanisms of such alterations are unknown. Here, we hypothesized that the undegraded substances found in this disease could be recognized as damage-associated molecular patterns (DAMPS), leading to activation of the inflammasome. Brains from 2 and 5 months normal and MPS II mice were studied. We observed an increase in cathepsin B activity in the brain tissue and leakage of this enzyme from the lysosome to the cytoplasm in a MPS II neuronal cell line, which is a known activator of the inflammasome. Furthermore, Caspase-1 activity and IL-1-beta levels were elevated at 5 months, confirming that this pathway is indeed altered. Our results suggest that undegraded GAG activate the inflammasome pathway in MPS II and future studies could focus on blocking such pathway to better understand the role of this process to the pathogenesis of MPS II.

Hunter 综合征或粘多糖贮积症 II 型 (MPS II) 是一种 X 连锁隐性疾病，由艾杜糖 2-硫酸酯酶 (IDS) 缺乏引起，导致未降解的乙酰肝素和硫酸皮肤素的储存。患有严重形式的患者会出现神经系统异常，但这种改变的机制尚不清楚。在这里，我们假设在这种疾病中发现的未降解物质可以被识别为损伤相关分子模式 (DAMPS)，从而导致炎症小体的激活。研究了 2 个月和 5 个月的正常小鼠和 MPS II 小鼠的大脑。我们观察到脑组织中组织蛋白酶 B 活性的增加以及这种酶从溶酶体泄漏到 MPS II 神经元细胞系中的细胞质，这是一种已知的炎性体激活剂。此外，Caspase-1 活性和 IL-1-β 水平在 5 个月时升高，证实该途径确实发生了改变。我们的研究结果表明，未降解的 GAG 激活了 MPS II 中的炎性体通路，未来的研究可以集中在阻断该通路上，以更好地了解该过程在 MPS II 发病机制中的作用。