Gene expression profile in patients with Gaucher disease indicates activation of inflammatory processes

Ługowska, Agnieszka; Hetmańczyk-Sawicka, Katarzyna; Iwanicka-Nowicka, Roksana; Fogtman, Anna; Cieśla, Jarosław M.; Purzycka-Olewiecka, Joanna Karolina; Sitarska, Dominika; Płoski, Rafał; Filocamo, Mirella; Lualdi, Susanna; Bednarska-Makaruk, Małgorzata; Koblowska, Marta

doi:10.1038/s41598-019-42584-1

Cited by 19 publications

(15 citation statements)

References 45 publications

(48 reference statements)

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“…In agreement with a recent publication by Lugowska et al using GD fibroblasts [ 18 ], we found that GD macrophages exhibited significant up-regulation of a number of other immune response genes, including IFIT1 , IFIT2 , MX1 , OAS2 , and LY6E [ 18 ]. Future experiments will explore whether any of these genes could be used as potential new GD biomarkers.…”

Section: Resultssupporting

confidence: 93%

“…GD patients are primed for oxidative response complications because they are known to have a severe redox imbalance partially caused by alterations in catalase activity [ 44 ]. While plasma from GD patients has elevated catalase enzymatic activity, GD RBCs have significantly lower catalase activity [ 18 , 45 ]. We found that unstimulated GD macrophages express significantly lower levels of CAT , the gene that encodes for catalase, than unstimulated control macrophages.…”

Section: Resultsmentioning

confidence: 99%

“…At the subcellular level, tubular structured lysosomes form in giant macrophages that become engorged with undigested lipid. Pathological macrophages have elevated expression of cytokines, chemokines, and complement, leading to chronic systemic inflammation [ 16 , 17 , 18 ]. Currently, the primary treatment for the visceral abnormalities of GD is enzyme replacement therapy (ERT) with recombinant glucocerebrosidase (rGCase), and more recently, substrate reduction therapy (SRT) with GluCer synthase inhibitors [ 1 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

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C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages

Serfecz

Saadin

Santiago

et al. 2021

IJMS

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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.

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Section: Resultssupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages

Serfecz

Saadin

Santiago

et al. 2021

IJMS

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“…Moreover, SPC may also be implicated in chronic vascular disease with involvement in processes such as proliferation and migration of vascular smooth muscle cells by acting as a pro-inflammatory mediator by activating p38 mitogen-activated protein kinases [ 36 ]. This is consistent with inflammation being involved in the pathogenesis of GD [ 37 ]. However, SPC (similar to N-palmitoyl-O-phosphocholineserine) is not specific to Gaucher disease.…”

Section: Resultssupporting

confidence: 87%

Identification of a Reliable Biomarker Profile for the Diagnosis of Gaucher Disease Type 1 Patients Using a Mass Spectrometry-Based Metabolomic Approach

Menkovic

Boutin

Alayoubi

et al. 2020

IJMS

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Gaucher disease (GD) is a rare autosomal recessive multisystemic lysosomal storage disorder presenting a marked phenotypic and genotypic variability. GD is caused by a deficiency in the glucocerebrosidase enzyme. The diagnosis of GD remains challenging because of the large clinical spectrum associated with the disease. Moreover, GD biomarkers are often not sensitive enough and can be subject to polymorphic variations. The main objective of this study was to perform a metabolomic study using an ultra-performance liquid chromatography system coupled to a time-of-flight mass spectrometer to identify novel GD biomarkers. Following the analysis of plasma samples from patients with GD, and age- and gender-matched control samples, supervised statistical analyses were used to find the best molecules to differentiate the two groups. Targeted biomarkers were structurally elucidated using accurate mass measurements and tandem mass spectrometry. This metabolomic study was successful in highlighting seven biomarkers associated with GD. Fragmentation tests revealed that these latter biomarkers were lyso-Gb1 (glucosylsphingosine) and four related analogs (with the following modifications on the sphingosine moiety: -C2H4, -H2, -H2+O, and +H2O), sphingosylphosphorylcholine, and N-palmitoyl-O-phosphocholineserine. Based on the plasma biomarker distribution, we suggest the evaluation of this GD biomarker profile, which might facilitate early diagnosis, monitoring, and follow-up of patients.

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“…The human ISLR protein, a member of the Ig superfamily, contains a leucine-rich repeat (LRR) with conserved flanking sequences and a C2type immunoglobulin (Ig)-like domain (Nagasawa et al, 1997). The ISLR protein has been reported to be involved in some biological events, such as cell replicative senescence of human dermal fibroblasts (Yoon et al, 2004), embryo development (Homma et al, 2009), and Gaucher disease (Lugowska et al, 2019). However, no study has mainly investigated the potential functional relationship between the ISLR gene and cancer events thus far.…”

Section: Introductionmentioning

confidence: 99%

An Analysis Regarding the Association Between the ISLR Gene and Gastric Carcinogenesis

Zhao²,

Sun

2020

Front. Genet.

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For datasets of gastric cancer collected by TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus) repositories, we applied a bioinformatics approach to obtain expression data for the ISLR (immunoglobulin superfamily containing leucine-rich repeat) gene, which is highly expressed in gastric cancer tissues and closely associated with clinical prognosis. Although we did not observe an overall association of ISLR mutation, high expression or copy number variation with survival, hypomethylation of four methylated sites (assessed by the probes cg05195566, cg17258195, cg09664357, and cg07297039) of ISLR was negatively correlated with high expression levels of ISLR and was associated with poor clinical prognosis. In addition, we detected a correlation between ISLR expression and the infiltration levels of several immune cells, especially CD8 + T cells, macrophages and dendritic cells. We also identified a series of genes that were positively and negatively correlated with ISLR expression based on the TCGA-STAD, GSE13861, and GSE29272 datasets. Principal component analysis and random forest analysis were employed to further screen for six hub genes, including ISLR, COL1A2, CDH11, SPARC, COL3A1, and COL1A1, which exhibited a good ability to differentiate between tumor and normal samples. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway and gene set enrichment analysis data also suggested a potential relationship between ISLR gene expression and epithelial-mesenchymal transition (EMT). ISLR expression was negatively correlated with sensitivity to PX-12 and NSC632839. Taken together, these results show that the ISLR gene is involved in gastric carcinogenesis, and the underlying molecular mechanisms may include DNA methylation, EMT, and immune cell infiltration.

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Gene expression profile in patients with Gaucher disease indicates activation of inflammatory processes

Cited by 19 publications

References 45 publications

C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages

C5a Activates a Pro-Inflammatory Gene Expression Profile in Human Gaucher iPSC-Derived Macrophages

Identification of a Reliable Biomarker Profile for the Diagnosis of Gaucher Disease Type 1 Patients Using a Mass Spectrometry-Based Metabolomic Approach

An Analysis Regarding the Association Between the ISLR Gene and Gastric Carcinogenesis

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