Upregulation of Proinflammatory Cytokines in the Fetal Brain of the Gaucher Mouse

Abstract

Gaucher disease is caused by a deficiency of glucocerebrosidase. Patients with Gaucher disease are divided into three major phenotypes: chronic nonneuronopathic, acute neuronopathic, and chronic neuronopathic, based on symptoms of the nervous system, the severity of symptoms, and the age of disease onset. The characteristics of patients with acute neuronopathic- and chronic neuronopathic type Gaucher disease include oculomotor abnormalities, bulbar signs, limb rigidity, seizures and occasional choreoathetoid movements, and neuronal loss. However, the mechanisms leading to the neurodegeneration of this disorder remain unknown. To investigate brain dysfunction in Gaucher disease, we studied the possible role of inflammation in neurodegeneration during development of Gaucher disease in a mouse model. Elevated levels of the proinflammatory cytokines, IL-1α, IL-1β, IL-6, and TNF-α, were detected in the fetal brains of Gaucher mice. Moreover, the levels of secreted nitric oxide and reactive oxygen species in the brains of Gaucher mice were higher than in wild-type mice. Thus, accumulated glucocerebroside or glucosylsphingosine, caused by glucocerebrosidase deficiency, may mediate brain inflammation in the Gaucher mouse via the elevation of proinflammatory cytokines, nitric oxide, and reactive oxygen species.

Severe Impairment of Regulatory T-Cells and Th1-Lymphocyte Polarization in Patients with Gaucher Disease

“…However, upregulation of the IFNg gene expression in CBE-treated mouse microglia (Hong et al 2006) or increased serum IFNg levels in GBA-deficient mice has been reported (Pandey et al 2012;Liu et al 2012). Therefore, the cause of increased presence of TH1 IFNgproducing cells, possibly resulting in increased serum IFNg levels of patients with GD, needs to be explored.…”

Targeting of Tumor Necrosis Factor Alpha Receptors as a Therapeutic Strategy for Neurodegenerative Disorders

“…Interestingly, in affected brain regions in an NP-C mouse model, the expression of different components in TNF-mediated apoptotic signaling was found to be increased, including that of TNF-α itself, TNFR1, and caspase-8 [180]. Gaucher disease patients showed elevated serum TNF-α levels, and in the fetal brains of a Gaucher disease mouse model, TNF-α levels (as well as the levels of different other pro-inflammatory cytokines) were increased [181,182]. Also, after birth, TNF-α and TNFR1 were found to be upregulated in the brains of Gaucher disease mice with increasing age and disease severity [183].…”

Neonatal Cholestasis as Initial Manifestation of Type 2 Gaucher Disease: A Continuum in the Spectrum of Early Onset Gaucher Disease

“…Various proinflammatory cytokines have been implicated in the pathogenesis of Gaucher disease including IL-1 (Gery et al 1981), TNF-alpha, IL-6, and IL-10 (Michelakakis et al 1996;Allen et al 1997). In the Gaucher mouse model, accumulation of glucocerebroside appears to mediate brain inflammation via proinflammatory cytokines (Hong et al 2006). This raises the possibility that the initial nonspecific clinical and histological features could be manifestations of a systemic inflammatory response (SIR) and as such harbinger of an inflammatory process ultimately resulting in the brain stem degeneration associated with the acute neuronopathic course of GD.…”