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Review
. 2019 Oct 18:10:2410.
doi: 10.3389/fimmu.2019.02410. eCollection 2019.

Long-Chain Acyl-CoA Synthetase 1 Role in Sepsis and Immunity: Perspectives From a Parallel Review of Public Transcriptome Datasets and of the Literature

Jessica Roelands  1   2 , Mathieu Garand  1 , Emily Hinchcliff  3 , Ying Ma  4 , Parin Shah  4 , Mohammed Toufiq  1 , Mohamed Alfaki  1 , Wouter Hendrickx  1 , Sabri Boughorbel  1 , Darawan Rinchai  1 , Amir Jazaeri  3 , Davide Bedognetti  1 , Damien Chaussabel  1
Affiliations
Review

Long-Chain Acyl-CoA Synthetase 1 Role in Sepsis and Immunity: Perspectives From a Parallel Review of Public Transcriptome Datasets and of the Literature

Jessica Roelands et al. Front Immunol. .

Abstract

A potential role for the long-chain acyl-CoA synthetase family member 1 (ACSL1) in the immunobiology of sepsis was explored during a hands-on training workshop. Participants first assessed the robustness of the potential gap in biomedical knowledge identified via an initial screen of public transcriptome data and of the literature associated with ACSL1. Increase in ACSL1 transcript abundance during sepsis was confirmed in several independent datasets. Querying the ACSL1 literature also confirmed the absence of reports associating ACSL1 with sepsis. Inferences drawn from both the literature (via indirect associations) and public transcriptome data (via correlation) point to the likely participation of ACSL1 and ACSL4, another family member, in inflammasome activation in neutrophils during sepsis. Furthermore, available clinical data indicate that levels of ACSL1 and ACSL4 induction was significantly higher in fatal cases of sepsis. This denotes potential translational relevance and is consistent with involvement in pathways driving potentially deleterious systemic inflammation. Finally, while ACSL1 expression was induced in blood in vitro by a wide range of pathogen-derived factors as well as TNF, induction of ACSL4 appeared restricted to flagellated bacteria and pathogen-derived TLR5 agonists and IFNG. Taken together, this joint review of public literature and omics data records points to two members of the acyl-CoA synthetase family potentially playing a role in inflammasome activation in neutrophils. Translational relevance of these observations in the context of sepsis and other inflammatory conditions remain to be investigated.

Keywords: OMICS data; lipid metabolism; long-chain acyl-CoA synthetase; neutrophils; sepsis.

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Figures

Figure 1
Figure 1
ACSL1 is upregulated by septic plasma. Abundance of ACSL1 transcripts was measured by microarray in neutrophils exposed in vitro for 6 h to plasma from uninfected control subjects or from patients with sepsis [from a dataset deposited in GEO by Khaenam et al. with unique identifier GSE49755 (7)]. Neutrophils were obtained from two different healthy donors, each exposed to the same set of plasma samples which consisted in plasma from 6 uninfected controls and 12 septic patients. Differences between groups were statistically significant (**p < 0.01), and confirmed in two independent test sets from the same study (GSE49756, GSE49757). ACSL1 profiles from all three datasets can be accessed via the GXB data browsing application: (–10). Design elements in this and subsequent figures obtained from http://www.clker.com/ (eppendorf tube) and https://www.vecteezy.com (red cross, DNA helix, cell).
Figure 2
Figure 2
Abundance of ACSL1 and ACSL4 transcripts is significantly increased in the context of sepsis in five out of seven datasets. Fold changes in abundance of ACSL1 and ACSL4 is shown in sepsis vs. control groups across multiple datasets (, –16). Each spot represents a single dataset, except for GSE49756/7 which shows averaged values for the GSE49756 and GSE49757 series and that also comprises GSE49755 (Figure 1). The position of the spot on the vertical axis indicates the corresponding fold change in abundance of ACSL1 (left) and ACSL4 (right). Spots are connected to dataset attributes (metadata). On the top panel attributes relevant to the group comparisons that were performed are shown (indicating which groups are being compared and whether increase in ACSLs abundance are statistically significant). On the middle and bottom panels additional attributes that describe the study populations and assays are shown.
Figure 3
Figure 3
Restriction of expression of ACSL family members transcripts in human leukocyte populations. Relative transcript abundance levels for the 5 members of the ACSL family are represented with cord plots for 7 different blood leukocyte populations. Expression data used to generate the plots were obtained from public domain RNAseq dataset with accession ID GSE60424 (93), with the exception pre-erythrocytes expression data, which was obtained from the BioGPS dataset (21). Each family member is represented by a different color: ACSL1 (red), ACSL2 (beige), ACSL4 (green), ACSL5 (blue), and ACSL6 (purple). The size of the circle is proportional to relative expression levels of ACSLs. For instance, expression in neutrophils was about four times higher than in monocytes and ten times higher than in other cell populations.
Figure 4
Figure 4
Induction of ACSL1 and ACSL4 expression in response to immune stimulation. The data presented here was generated by Obermoser et al. (GSE30101) (102). The box plots show levels of abundance of ACSL1 and ACSL4 in whole blood of four healthy subjects incubated for 6 h. at 37°C with 18 different immune stimuli or left unstimulated. Conditions included Toll-like receptors agonists PAM3, Zymosan, Poly IC, E-LPS, Flagellin, R837, CpG Type A, heat-killed Escherichia coli (HK E. coli), heat-killed Legionella pneumophila (HKLP), heat-killed Acholeplasma laidlawii (HKAL), and heat-killed Staphylococcus aureus (HKSA); live influenza A virus (Flu) and live respiratory syncytial virus (RSV), and the host-derived immunostimulatory molecules IL18, TNF-α, IFN-α2b, IFN-β, IFN-γ.
Figure 5
Figure 5
Correlation matrix for a set of genes constituting a blood transcriptional module associated functionally with neutrophil-driven inflammation (M13.12). The blood transcriptional module is part of a recently described repertoire constructed on the basis of co-expression across a 16 different immune/pathological states (described in the text). The list of genes constituting this module (M13.12) comprised ACSL1. The matrix represents degree of correlation calculated for each gene pair for the septic plasma neutrophil exposure dataset.
Figure 6
Figure 6
Clinical significance of increases in ACSL1, ACSL4, and Inflammasome genes in the septic plasma neutrophil exposure dataset. For this figure all three datasets from this dataset series published as part of the work of Khaenam et al. were combined (see text for details). Fold changes over average of cells cultured with medium only are shown. Available clinical information was used to assign sepsis subjects to either one of three groups: Recovered, Not improved and Dead. Significance between the different groups is indicated above each graph with t-test *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.
Figure 7
Figure 7
Inferred role of ACSL1 in sepsis. The experimental context in which the increase in ACSL1 expression was initially observed is represented in the panel above (GSE49755). Open questions include: #1 What are the factors in the plasma of septic patients that induce ACSL1 expression in neutrophils? #2 Which signaling pathway is involved in regulation of ACSL1 following plasma exposure? #3 What is the role of ACSL1 in sepsis? Regarding question #1 (arrows down): briefly as suggested by the data presented on Figure 4 ACSL1 is induced in blood by a wide range of pathogen-derived factors and ACSL4 by a narrower range of factors (putatively attributed to the flagellated bacteria TLR5 agonist, flagellin). Regarding question #2 (oblique arrow): ACSL1 is known to contribute to the activation of inflammasomes in macrophages, which in turn leads to release of proinflammatory factors (116). Based on differential and co-expression analyses we infer that it might also be the case of ACSL4, for instance during responses to infection caused by flagellated bacteria. We also infer that ACSL-mediated inflammasome activation operates in neutrophils and also in the context of sepsis, which are also points that remain to be established. Neutrophil contribution to the cytokine storm observed during sepsis and subsequent immunopathology is well-documented. We thus assume that upregulation of ACSL1 observed during sepsis is of potential clinical relevance. An assertion that is supported by differential levels of induction observed following exposure to plasma of subject who recovered vs. those who died (Figure 6).
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