Lysosomal storage and impaired autophagy lead to inflammasome activation in Gaucher macrophages.
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.
Section of Molecular Neurogenetics, National Human Genome Research Institute, Bethesda, MD, 20892, USA.
Elma
E
Aflaki
Section of Molecular Neurogenetics, National Human Genome Research Institute, Bethesda, MD, 20892, USA.
Nima
N
Moaven
Section of Molecular Neurogenetics, National Human Genome Research Institute, Bethesda, MD, 20892, USA.
Daniel K
DK
Borger
Section of Molecular Neurogenetics, National Human Genome Research Institute, Bethesda, MD, 20892, USA.
Grisel
G
Lopez
Section of Molecular Neurogenetics, National Human Genome Research Institute, Bethesda, MD, 20892, USA.
Wendy
W
Westbroek
Inflammatory Disease Section, National Human Genome Research Institute, Bethesda, MD, 20892, USA.
Jae Jin
JJ
Chae
National Center for Advancing Translational Science, National Institutes of Health, Bethesda, MD, 20892, USA.
Juan
J
Marugan
National Center for Advancing Translational Science, National Institutes of Health, Bethesda, MD, 20892, USA.
Samarjit
S
Patnaik
Section of Molecular Neurogenetics, National Human Genome Research Institute, Bethesda, MD, 20892, USA.
Emerson
E
Maniwang
Section of Molecular Neurogenetics, National Human Genome Research Institute, Bethesda, MD, 20892, USA.
Ashley N
AN
Gonzalez
Section of Molecular Neurogenetics, National Human Genome Research Institute, Bethesda, MD, 20892, USA.
Ellen
E
Sidransky
D000328:Adult; D000368:Aged; D001343:Autophagy / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology*; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology*; D016328:NF-kappa B / Q000378:metabolism
D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B
Gaucher disease; autophagy; glucocerebrosidase; inflammasome; interleukin-1β; lysosome; macrophage