C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages
Gaucher disease (GD) is an autosomal recessive disorder caused by bi-allelic <i>GBA1</i> 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 ce...
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doaj-43f08b6566b646268629b3a0f21c35e12021-09-26T00:23:39ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-09-01229912991210.3390/ijms22189912C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived MacrophagesJacquelyn C. Serfecz0Afsoon Saadin1Clayton P. Santiago2Yuji Zhang3Søren M. Bentzen4Stefanie N. Vogel5Ricardo A. Feldman6Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USAThe Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USADepartment of Epidemiology and Public Health, University of Maryland, Baltimore, MD 21201, USADepartment of Epidemiology and Public Health, University of Maryland, Baltimore, MD 21201, USADepartment of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USAGaucher disease (GD) is an autosomal recessive disorder caused by bi-allelic <i>GBA1</i> 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.https://www.mdpi.com/1422-0067/22/18/9912gaucher diseaseinduced pluripotent stem cells (iPSC)macrophagescomplementC5ainflammation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jacquelyn C. Serfecz Afsoon Saadin Clayton P. Santiago Yuji Zhang Søren M. Bentzen Stefanie N. Vogel Ricardo A. Feldman |
spellingShingle |
Jacquelyn C. Serfecz Afsoon Saadin Clayton P. Santiago Yuji Zhang Søren M. Bentzen Stefanie N. Vogel Ricardo A. Feldman C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages International Journal of Molecular Sciences gaucher disease induced pluripotent stem cells (iPSC) macrophages complement C5a inflammation |
author_facet |
Jacquelyn C. Serfecz Afsoon Saadin Clayton P. Santiago Yuji Zhang Søren M. Bentzen Stefanie N. Vogel Ricardo A. Feldman |
author_sort |
Jacquelyn C. Serfecz |
title |
C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages |
title_short |
C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages |
title_full |
C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages |
title_fullStr |
C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages |
title_full_unstemmed |
C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages |
title_sort |
c5a activates a pro-inflammatory gene expression profile in human gaucher ipsc-derived macrophages |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-09-01 |
description |
Gaucher disease (GD) is an autosomal recessive disorder caused by bi-allelic <i>GBA1</i> 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. |
topic |
gaucher disease induced pluripotent stem cells (iPSC) macrophages complement C5a inflammation |
url |
https://www.mdpi.com/1422-0067/22/18/9912 |
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