CD14 regulates the metabolomic profiles of distinct macrophage subsets under steady and activated states

Macedo, Luana Henrique de; Souza, Camila Oliveira Silva; Gardinassi, Luiz Gustavo; Faccioli, Lúcia Helena

doi:10.1016/j.imbio.2022.152191

Cited by 7 publications

(5 citation statements)

References 39 publications

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“…We also observed upregulation (log2FC 1.9) of CD14 transcripts in blood from stage 2 r-HAT patients. CD14 is involved in activation of macrophages and regulation of macrophage metabolic profiles (38), which was consistent with our finding of activated lipid metabolic process, lipid transport and cellular amino acid metabolic process in stage 2 blood only (Fig…”

Section: Discussionsupporting

confidence: 92%

Distinct Differences in Gene Expression Profiles in Early and Late Stage Rhodesiense HAT Individuals in Malawi

Nambala

Mulindwa

Noyes

et al. 2022

Preprint

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T. b. rhodesiense is the causative agent of rhodesian Human African trypanosomiasis (r-HAT) in Malawi. Clinical presentation of r-HAT in Malawi varies between the different foci and differs from East African HAT clinical phenotypes. The purpose of this study was to gain more insights into the transcriptomic profiles of patients with early stage 1 and late stage 2 HAT disease in Malawi. Whole blood from individuals infected with T. b. rhodesiense was used for RNA-Seq. Control samples were from healthy trypanosome negative individuals matched on sex, age range, and disease focus. Illumina sequence FASTQ reads were aligned to the GRCh38 release 84 human genome sequence using HiSat2 and differential analysis was done in R using the DESeq2 package. XGR, ExpressAnalyst and InnateDB algorithms were used for functional annotation and gene enrichment analysis of significant differentially expressed genes. RNA-seq was done on 25 healthy controls and 23 r-HAT case samples of which 3 case samples were excluded for downstream analysis as outliers. 4519 genes were significantly differentially expressed (p adjusted <0.05) in individuals with early stage 1 r-HAT disease (n = 12) and 1824 genes in individuals with late stage 2 r-HAT disease (n = 8). Enrichment of innate immune response genes through neutrophil activation was identified in individuals with both early and late stages of the disease. Additionally, lipid metabolism genes were enriched in late stage 2 disease. We further identified uniquely upregulated genes (log2 Fold Change 1.4 - 2.0) in stage 1 (ZNF354C) and stage 2 (TCN1 and MAGI3) blood. Our data brings new insight into the human transcriptome landscape during T. b. rhodesiense infection. We have further identified key biological pathways and transcripts during stage 1 and stage 2 r-HAT. Lastly, we have identified potential diagnostic biomarkers that may be used for staging of r-HAT disease.

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Section: Discussionsupporting

confidence: 92%

Distinct Differences in Gene Expression Profiles in Early and Late Stage Rhodesiense HAT Individuals in Malawi

Nambala

Mulindwa

Noyes

et al. 2022

Preprint

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“…The main source of IL21 is T follicular helper cells which are a subset of CD4+ T cells which stimulate T-cell dependent humoral immunity, and in the current study, we observed upregulation (log2FC 1.9) of CD14+ T cell transcripts in blood from stage 2 r-HAT patients. CD14+ T cells are also involved in activation of macrophages and regulation of macrophage metabolic profiles [25], which may be consistent with our finding of IL21 upregulation, activated lipid metabolic process, lipid transport and cellular amino acid metabolic process in stage 2 blood only (Fig 3B).…”

Section: Plos Neglected Tropical Diseasessupporting

confidence: 92%

Differences in gene expression profiles in early and late stage rhodesiense HAT individuals in Malawi

Nambala,

Mulindwa,

Noyes

et al. 2023

PLoS Negl Trop Dis

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T. b. rhodesiense is the causative agent of Rhodesian human African trypanosomiasis (r-HAT) in Malawi. Clinical presentation of r-HAT in Malawi varies between foci and differs from East African HAT clinical phenotypes. The purpose of this study was to gain more insights into the transcriptomic profiles of patients with early stage 1 and late stage 2 HAT disease in Malawi. Whole blood from individuals infected with T. b. rhodesiense was used for RNA-Seq. Control samples were from healthy trypanosome negative individuals matched on sex, age range, and disease foci. Illumina sequence FASTQ reads were aligned to the GRCh38 release 84 human genome sequence using HiSat2 and differential analysis was done in R Studio using the DESeq2 package. XGR, ExpressAnalyst and InnateDB algorithms were used for functional annotation and gene enrichment analysis of significant differentially expressed genes. RNA-seq was done on 23 r-HAT case samples and 28 healthy controls with 7 controls excluded for downstream analysis as outliers. A total of 4519 genes were significant differentially expressed (p adjusted <0.05) in individuals with early stage 1 r-HAT disease (n = 12) and 1824 genes in individuals with late stage 2 r-HAT disease (n = 11) compared to controls. Enrichment of innate immune response genes through neutrophil activation was identified in individuals with both early and late stages of the disease. Additionally, lipid metabolism genes were enriched in late stage 2 disease. We further identified uniquely upregulated genes (log2 Fold Change 1.4–2.0) in stage 1 (ZNF354C) and stage 2 (TCN1 and MAGI3) blood. Our data add to the current understanding of the human transcriptome profiles during T. b. rhodesiense infection. We further identified biological pathways and transcripts enriched than were enriched during stage 1 and stage 2 r-HAT. Lastly, we have identified transcripts which should be explored in future research whether they have potential of being used in combination with other markers for staging or r-HAT.

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“…More precisely, arginine (Ratio T06/T02: 0.71), proline (Ratio T06/T02:0.64), ornithine (Ratio T06/T02: 0.71) and glutamine (Ratio T06/T02: 0.65) concentrations were decreased, contrary to those of spermidine, a product from the polyamine synthesis part ( Figure 7 and Figure 8 and Table S5 ). Arginine consumption was observed in many pro-inflammatory macrophages [ 55 , 56 , 57 ] and was due to the action of the enzyme iNOS allowing the production of NO and citrulline. Here, no significant change over time was observed for citrulline ( Figure 8 ), suggesting that arginine degradation is preferentially mediated by Arginase 1 (ARG1) for the production of ornithine which can be metabolized to putrescine by the ornithine decarboxylase 1 (ODC1) enzyme.…”

Section: Resultsmentioning

confidence: 99%

Development of an Untargeted Metabolomics Strategy to Study the Metabolic Rewiring of Dendritic Cells upon Lipopolysaccharide Activation

et al. 2023

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Dendritic cells (DCs) are essential immune cells for defense against external pathogens. Upon activation, DCs undergo profound metabolic alterations whose precise nature remains poorly studied at a large scale and is thus far from being fully understood. The goal of the present work was to develop a reliable and accurate untargeted metabolomics workflow to get a deeper insight into the metabolism of DCs when exposed to an infectious agent (lipopolysaccharide, LPS, was used to mimic bacterial infection). As DCs transition rapidly from a non-adherent to an adherent state upon LPS exposure, one of the leading analytical challenges was to implement a single protocol suitable for getting comparable metabolomic snapshots of those two cellular states. Thus, a thoroughly optimized and robust sample preparation method consisting of a one-pot solvent-assisted method for the simultaneous cell lysis/metabolism quenching and metabolite extraction was first implemented to measure intracellular DC metabolites in an unbiased manner. We also placed special emphasis on metabolome coverage and annotation by using a combination of hydrophilic interaction liquid chromatography and reverse phase columns coupled to high-resolution mass spectrometry in conjunction with an in-house developed spectral database to identify metabolites at a high confidence level. Overall, we were able to characterize up to 171 unique meaningful metabolites in DCs. We then preliminarily compared the metabolic profiles of DCs derived from monocytes of 12 healthy donors upon in vitro LPS activation in a time-course experiment. Interestingly, the resulting data revealed differential and time-dependent activation of some particular metabolic pathways, the most impacted being nucleotides, nucleotide sugars, polyamines pathways, the TCA cycle, and to a lesser extent, the arginine pathway.

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CD14 regulates the metabolomic profiles of distinct macrophage subsets under steady and activated states

Cited by 7 publications

References 39 publications

Distinct Differences in Gene Expression Profiles in Early and Late Stage Rhodesiense HAT Individuals in Malawi

Distinct Differences in Gene Expression Profiles in Early and Late Stage Rhodesiense HAT Individuals in Malawi

Differences in gene expression profiles in early and late stage rhodesiense HAT individuals in Malawi

Development of an Untargeted Metabolomics Strategy to Study the Metabolic Rewiring of Dendritic Cells upon Lipopolysaccharide Activation

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