Abstract
Gaucher disease (GD) is an autosomal recessive disorder caused by bi-allelic GBA1 mutations that reduce the activity of the lysosomal enzyme β-glucocerebrosidase (GCase). GCase catalyzes the conversion of glucosylceramide (GluCer), a ubiquitous glycosphingolipid, to glucose and ceramide. GCase deficiency causes the accumulation of GluCer and its metabolite glucosylsphingosine (GluSph) in a number of tissues and organs. In the immune system, GCase deficiency deregulates signal transduction events, resulting in an inflammatory environment. It is known that the complement system promotes inflammation, and complement inhibitors are currently being considered as a novel therapy for GD; however, the mechanism by which complement drives systemic macrophage-mediated inflammation remains incompletely understood. To help understand the mechanisms involved, we used human GD-induced pluripotent stem cell (iPSC)-derived macrophages. We found that GD macrophages exhibit exacerbated production of inflammatory cytokines via an innate immune response mediated by receptor 1 for complement component C5a (C5aR1). Quantitative RT-PCR and ELISA assays showed that in the presence of recombinant C5a (rC5a), GD macrophages secreted 8–10-fold higher levels of TNF-α compared to rC5a-stimulated control macrophages. PMX53, a C5aR1 blocker, reversed the enhanced GD macrophage TNF-α production, indicating that the observed effect was predominantly C5aR1-mediated. To further analyze the extent of changes induced by rC5a stimulation, we performed gene array analysis of the rC5a-treated macrophage transcriptomes. We found that rC5a-stimulated GD macrophages exhibit increased expression of genes involved in TNF-α inflammatory responses compared to rC5a-stimulated controls. Our results suggest that rC5a-induced inflammation in GD macrophages activates a unique immune response, supporting the potential use of inhibitors of the C5a-C5aR1 receptor axis to mitigate the chronic inflammatory abnormalities associated with GD.
Highlights
We show that recombinant C5a activates a significant TNF-α inflammation response in human Gaucher disease (GD) macrophages, which is similar to that seen in animal models of GD [21]
We identify a set of differentially expressed genes (DEGs) between unstimulated GD and control macrophages
As global transcriptome changes have not been previously studied in human Gaucher macrophages or in the context of recombinant human C5a (rC5a) stimulation, our results represent an important step in understanding how C5a-C5aR1 axis stimulation contributes to chronic inflammation in GD patients
Summary
Pathological macrophages have elevated expression of cytokines, chemokines, and complement, leading to chronic systemic inflammation [16,17,18]. The increased C5a levels detected in GD patient sera are thought to result from the presence of GluCer-specific auto-antibody immune complexes (IC) that activate the classical pathway of the complement system [21]. Elevated complement component C5a causes the release of TNF-α and other pro-inflammatory mediators by macrophages, leading to chronic inflammation [21,28,29,30,31]. In addition to the adaptive immune response mediated by interactions of B cells and T cells with macrophages, there is an aberrant innate immune component caused by increased C5a levels alone, which is the focus of this study. Our results further suggest that C5a-C5aR1-inhibiting therapies may lessen the risk of potentiated inflammation, thereby diminishing the pathologies caused by overabundant C5a present in GD patient sera [21]
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