C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages
| Autor: | Afsoon Saadin, Clayton Santiago, Ricardo A. Feldman, Yuji Zhang, Søren M. Bentzen, Stefanie N. Vogel, Jacquelyn C Serfecz |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
β-glucocerebrosidase
C5a QH301-705.5 Induced Pluripotent Stem Cells gene arrays GBA1 Complement C5a Inflammation induced pluripotent stem cells (iPSC) Article Catalysis Cell Line Proinflammatory cytokine Inorganic Chemistry Immune system gaucher disease medicine Humans Macrophage complement Biology (General) Physical and Theoretical Chemistry QD1-999 Receptor Anaphylatoxin C5a Wnt Signaling Pathway Molecular Biology Spectroscopy Innate immune system Tumor Necrosis Factor-alpha Chemistry Gene Expression Profiling Organic Chemistry General Medicine Recombinant Proteins macrophages Computer Science Applications Complement system Cell biology Gene Expression Regulation inflammation Tumor necrosis factor alpha medicine.symptom Signal transduction Oxidation-Reduction TNF-alpha |
| Zdroj: | International Journal of Molecular Sciences Volume 22 Issue 18 International Journal of Molecular Sciences, Vol 22, Iss 9912, p 9912 (2021) |
| ISSN: | 1422-0067 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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