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Review
. 2020 Dec;161(4):291-302.
doi: 10.1111/imm.13239. Epub 2020 Aug 31.

Annexin A3 in sepsis: novel perspectives from an exploration of public transcriptome data

Mohammed Toufiq  1 , Jessica Roelands  1 , Mohamed Alfaki  1 , Basirudeen Syed Ahamed Kabeer  1 , Marwa Saadaoui  1 , Arun Prasath Lakshmanan  1 , Dhinoth Kumar Bangarusamy  1 , Selvasankar Murugesan  1 , Davide Bedognetti  1 , Wouter Hendrickx  1 , Souhaila Al Khodor  1 , Annalisa Terranegra  1 , Darawan Rinchai  1 , Damien Chaussabel  1 , Mathieu Garand  1
Affiliations
Review

Annexin A3 in sepsis: novel perspectives from an exploration of public transcriptome data

Mohammed Toufiq et al. Immunology. 2020 Dec.

Abstract

According to publicly available transcriptome datasets, the abundance of Annexin A3 (ANXA3) is robustly increased during the course of sepsis; however, no studies have examined the biological significance or clinical relevance of ANXA3 in this pathology. Here we explored this interpretation gap and identified possible directions for future research. Based on reference transcriptome datasets, we found that ANXA3 expression is restricted to neutrophils, is upregulated in vitro after exposure to plasma obtained from septic patients, and is associated with adverse clinical outcomes. Secondly, an increase in ANXA3 transcript abundance was also observed in vivo, in the blood of septic patients in multiple independent studies. ANXA3 is known to mediate calcium-dependent granules-phagosome fusion in support of microbicidal activity in neutrophils. More recent work has also shown that ANXA3 enhances proliferation and survival of tumour cells via a Caspase-3-dependent mechanism. And this same molecule is also known to play a critical role in regulation of apoptotic events in neutrophils. Thus, we posit that during sepsis ANXA3 might either play a beneficial role, by facilitating microbial clearance and resolution of the infection; or a detrimental role, by prolonging neutrophil survival, which is known to contribute to sepsis-mediated organ damage.

Keywords: annexin; bacteremia; cell proliferation; endotoxemia; immunity; inflammation; neutrophil; sepsis; transcriptome.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Annexin A3 (ANXA3) is upregulated in septic individuals and in cultured cells exposed to serum/plasma isolated from septic patients. The plots represent ANXA3 transcript abundance, as measured by microarray across different publicly available datasets (see text and Table 1). The three plots along the top correspond to independent replications of an experiment in which neutrophils in culture were exposed to plasma from uninfected control subjects or septic patients for 6 hr (deposited in GEO by Khaenam et al. under the GEO ID GSE49755/56/57). The GSE64457 data show the ANXA3 transcript abundance in neutrophils isolated from patients diagnosed with septic shock and neutrophils from healthy controls. The data presented in all other plots derived from studies that profiled the whole blood of septic patients and uninfected controls (all involved paediatric populations except for GSE13015). The level of statistical significance is indicated on each plot: t‐test P‐values < 0·05*, < 0·01**, < 0·001***.
Figure 2
Figure 2
Annexin A3 (ANXA3) upregulation in neutrophils in response to septic plasma correlates with clinical outcomes. The three independent datasets contributed by Khaenam et al. (GSE49755/56/57) were combined after normalizing each to the average of its respective controls (neutrophil cultures with medium only). Other conditions included cells exposed to LPS or to plasma from: (i) uninfected controls; (ii) septic patients who responded to treatment and eventually recovered; and (iii) septic patients who did not improve and ultimately succumbed to sepsis. The level of statistical significance is indicated on the plot: t‐test P‐values < 0·01**, < 0·001***.
Figure 3
Figure 3
Annexin A3 (ANXA3) shows the most restricted expression to neutrophils of all Annexin family member transcripts. Each chord diagram (circle) presents the relative transcript abundance for a given gene across six leucocyte populations: neutrophils, monocytes, B‐cells, CD4 T‐cells, CD8 T‐cells and NK cells. The colours assigned to each cell population are shown on the ANXA3 diagram (bottom). The predominance of a given colour in a diagram indicates a tendency of expression of the Annexin family member to be preferentially restricted to a given leucocyte population. ANXA3 is predominantly coloured red, indicating the restricted expression of this transcript to neutrophils. Conversely, ANXA2 and ANXA5 are predominantly coloured orange, indicating the preferentially restricted expression of these transcripts to monocytes. Placement of the diagrams along the y‐axis indicates the average abundance levels (expressed as normalized counts) of each Annexin family member. Placement along the x‐axis reflects the arrangement in descending order of average intensity. The segments on the right are partitioned by cell type, and their size is determined according to the average counts of each population across the 20 study subjects [14 in the case of natural killer (NK) cells]. The ribbons for each segment on the right connect to the same segment on the left, which consists of the sum of average counts (cum. counts). The plots were generated using the ‘Circlize’ R package. 58 Levels of expression of ANXA3 in neutrophils were found to be significantly higher than in all other cell types (P < 0·001; interactive box plot: http://sepsis.gxbsidra.org/dm3/miniURL/view/Pv).
Figure 4
Figure 4
Annexin A3 (ANXA3) transcript abundance in vitro changes after exposure to certain immunostimulatory molecules. This reference dataset was contributed to GEO by our group. 59 Fresh whole blood samples from four healthy subjects were incubated for 6 hr at 37° with one of 18 different stimuli or left unstimulated. The RNAs were then stabilized with Tempus reagent and extracted before processing for microarray analysis. The stimulation conditions included: PAM3, Zymosan, Poly IC, E‐LPS, Flagellin, R837, CpG Type A, heat‐killed Legionella pneumophila (HKLP), heat‐killed Acholeplasma laidlawii (HKAL), and heat‐killed Staphylococcus aureus (HKSA) (all from Invivogen); IL‐18, TNF‐α, IFN‐α2b, IFN‐β, IFN‐γ (all from Peprotech); heat‐killed Escherichia coli (in house preparation), live influenza A virus and live respiratory syncytial virus (RSV). Levels of expression under stimulation by interferon (IFN‐α2b, IFN‐β, IFN‐γ) were found to be significantly higher than in all other conditions (t‐test, P < 0·05).
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