Lysosomal storage and impaired autophagy lead to inflammasome activation in G aucher macrophages

• DOI: 10.1111/acel.12409
• Publication Date: 2015-10-22T03:43:03Z
• Authors: Elma Aflaki; Nima Moaven; Daniel K. Borger; Grisel Lopez; Wendy Westbroek; Jae Jin Chae; Juan Marugan; Samarjit Patnaik; Emerson Maniwang; Ashley N. Gonzalez; Ellen Sidransky
• Keywords: Proinflammatory cytokine

Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, is characterized by presence glucosylcer-amide macrophages, accumulation glucosylceramide in lysosomes and secretion inflammatory cytokines. However, connection between this storage inflammation not clear. Studying macrophages derived from peripheral monocytes patients with type 1 disease genotype N370S/N370S, we confirmed an increased interleukins IL-1β IL-6. In addition, found that activation inflammasome, a multiprotein complex activates caspase-1, led to maturation macrophages. We show inflammasome these cells result impaired autophagy. Treatment small-molecule glucocerebrosidase chaperone NCGC758 reversed defects, inducing autophagy reducing secretion, confirming role processes. elevated levels autophagic adaptor p62 prevented delivery inflammasomes autophagosomes. This increase p65-NF-kB nucleus, promoting expression cytokines IL-1β. newly elucidated mechanism ties dysfunction activation, may contribute massive organomegaly, bone involvement susceptibility certain malignancies seen disease. Moreover, link storage, autophagy, have implications relevant both Parkinson aging process. Defects basic cellular processes also provide new therapeutic targets.