Abstract
Gaucher’s disease is caused by defects in acid β-glucosidase 1 (GBA1) and has been also proposed as an inflammatory disease. GBA1 cleaves glucosylceramide to form ceramide, an established bioactive lipid, and defects in GBA1 lead to aberrant accumulation in glucosylceramide and insufficient formation of ceramide. We investigated if the pro-inflammatory kinase p38 is activated in Gaucher’s disease, since ceramide has been proposed to suppress p38 activation. Three Gaucher’s disease mouse models were employed, and p38 was found to be activated in lung and liver tissues of all Gaucher’s disease mice. Most interestingly, neuronopathic Gaucher’s disease type mice, but not non-neuronopathic ones, displayed significant activation of p38 and up-regulation of p38-inducible proinflammatory cytokines in brain tissues. In addition, all type of Gaucher’s disease mice also showed increases in serum IL-6. As cellular signalling is believed to represent an in vivo inflammatory phenotype in Gaucher’s disease, activation of p38 and possibly its-associated formation of proinflammatory cytokines were assessed in fibroblasts established from neuronopathic Gaucher’s disease mice. In mouse Gaucher’s disease cells, p38 activation and IL-6 formation by TNF-α treatment were enhanced as compared to those of wild type. Furthermore, human fibroblasts from Gaucher’s disease patients also displayed increases in p38 activation and IL-6 formation as comparison to healthy counterpart. These results raise the potential that proinflammatory responses such as p38 activation and IL-6 formation are augmented in Gaucher’s disease.
Highlights
Gaucher’s disease is the most common lysosomal storage disorder caused by mutations in a gene encoding a lysosomal enzyme, acid β-glucosidase 1 (GBA1) [1,2,3,4,5]
The classical hallmark of the disease is the presence of the Gaucher cell, a macrophage containing much of the stored glucosylceramide found in tissues, which is believed to cause the clinical manifestations of the disease
Human fibroblasts established from patients with Gaucher’s disease and healthy volunteer were grown in α-MEM medium supplemented with 10–15% fetal bovine serum (FBS)
Summary
Gaucher’s disease is the most common lysosomal storage disorder caused by mutations in a gene encoding a lysosomal enzyme, acid β-glucosidase 1 (GBA1) [1,2,3,4,5]. The classical hallmark of the disease is the presence of the Gaucher cell, a macrophage containing much of the stored glucosylceramide found in tissues, which is believed to cause the clinical manifestations of the disease. The pathogenesis of Gaucher’s disease appears to extend beyond simple accumulation of glucosylceramide in Gaucher cells and seems to involve systemic inflammatory responses [8, 9]. Insufficient formation of ceramide caused by GBA1 defects was assumed to promote p38 activation and its-driven inflammatory responses in Gaucher’s disease. We assessed if p38 is activated in Gaucher’s disease in vivo and in vitro. Those studies provide insight for potential anti-inflammatory therapy targeting p38 for Gaucher’s disease
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