Abstract
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.
Highlights
In Gaucher disease (GD), the most common lysosomal storage disorder, macrophages accumulate glycolipids within lysosomes due to the defective digestion of aged erythrocytes and senescent leukocytes (Lee, 1968)
There was only modest secretion of IL-1b in Gaucher and control peripheral blood monocytes (PBMCs) treated with LPS alone, but IL-1b secretion increased significantly when LPS was supplemented with ATP, a potent activator of NLRP3
Increased levels of IL-6 were detected in lysates from Gaucher macrophages (GMs) treated with either LPS alone or LPS with ATP, compared to control macrophages (Fig. 1C)
Summary
In Gaucher disease (GD), the most common lysosomal storage disorder, macrophages accumulate glycolipids within lysosomes due to the defective digestion of aged erythrocytes and senescent leukocytes (Lee, 1968). The disease results from a deficiency of the lysosomal enzyme glucocerebrosidase (GCase), which cleaves a glucose moiety from the glycolipid glucosylceramide (GluCer). This lysosomal storage leads to the characteristic engorged macrophages, known as Gaucher macrophages (GMs) or ‘Gaucher cells’ (Machaczka et al, 2011), and contributes to the organomegaly, bone disease and cytopenia typically encountered in patients with GD. Macroautophagy is a proteolytic process whereby organelles and cellular proteins are encapsulated and delivered to lysosomes (Mizushima & Komatsu, 2011) This form of autophagy takes place in three phases: induction, autophagosome formation, and degradation.
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