Lysosomal storage and impaired autophagy lead to inflammasome activation in Gaucher macrophages.
Lysosomal storage and impaired autophagy lead to inflammasome activation in Gaucher macrophages.
复制标题
溶酶体储存和受损的自噬导致戈谢氏巨噬细胞中的炎性小体激活。
DOI：
10.1111/acel.12409
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发表时间：
2016-02
期刊：
影响因子：
7.8
通讯作者：
Sidransky E
中科院分区：
文献类型：
--
作者：
Aflaki E;Moaven N;Borger DK;Lopez G;Westbroek W;Chae JJ;Marugan J;Patnaik S;Maniwang E;Gonzalez AN;Sidransky E
戈谢病是一种遗传性溶酶体糖脑苷酶缺乏症，其特征是存在糖基酰胺巨噬细胞，溶酶体中糖基神经酰胺的积累和炎症细胞因子的分泌。然而，这种溶酶体储存与炎症之间的联系尚不清楚。通过研究基因型为N370S/N370S的1型戈谢病患者外周血单核细胞衍生的巨噬细胞，我们证实了白细胞介素IL‐1β和IL‐6的分泌增加。此外，我们发现炎性小体（一种激活caspase‐1的多蛋白复合物）的激活导致高切巨噬细胞中IL‐1β的成熟。我们发现这些细胞中的炎性体活化是自噬受损的结果。用小分子糖脑苷酶伴侣NCGC758治疗可逆转这些缺陷，诱导自噬并减少IL - 1β分泌，证实了溶酶体糖脑苷酶缺乏在这些过程中的作用。我们发现，在高谢氏巨噬细胞中，自噬接头p62水平的升高阻止了炎症小体向自噬小体的传递。p62的增加导致细胞核中p65‐NF‐kB的激活，促进炎症细胞因子的表达和IL‐1β的分泌。这一新阐明的机制将溶酶体功能障碍与炎性体激活联系起来，并可能导致戈谢病中出现的大量器官肿大、骨骼受累和对某些恶性肿瘤的易感性增加。此外，溶酶体储存、自噬受损和炎症之间的这种联系可能与帕金森病和衰老过程有关。这些基本细胞过程中的缺陷也可能提供新的治疗靶点。
Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, is characterized by the presence of glucosylcer‐amide macrophages, the accumulation of glucosylceramide in lysosomes and the secretion of inflammatory cytokines. However, the connection between this lysosomal storage and inflammation is not clear. Studying macrophages derived from peripheral monocytes from patients with type 1 Gaucher disease with genotype N370S/N370S, we confirmed an increased secretion of interleukins IL‐1β and IL‐6. In addition, we found that activation of the inflammasome, a multiprotein complex that activates caspase‐1, led to the maturation of IL‐1β in Gaucher macrophages. We show that inflammasome activation in these cells is the result of impaired autophagy. Treatment with the small‐molecule glucocerebrosidase chaperone NCGC758 reversed these defects, inducing autophagy and reducing IL‐1β secretion, confirming the role of the deficiency of lysosomal glucocerebrosidase in these processes. We found that in Gaucher macrophages elevated levels of the autophagic adaptor p62 prevented the delivery of inflammasomes to autophagosomes. This increase in p62 led to activation of p65‐NF‐kB in the nucleus, promoting the expression of inflammatory cytokines and the secretion of IL‐1β. This newly elucidated mechanism ties lysosomal dysfunction to inflammasome activation, and may contribute to the massive organomegaly, bone involvement and increased susceptibility to certain malignancies seen in Gaucher disease. Moreover, this link between lysosomal storage, impaired autophagy, and inflammation may have implications relevant to both Parkinson disease and the aging process. Defects in these basic cellular processes may also provide new therapeutic targets.