Sepsis is characterized by high morbidity and mortality and is part of a complex clinical continuum (along with systemic inflammation and septic shock) that is associated with the dysregulation of the systemic immune response to an infection.1 As is the case with other inflammatory syndromes, sepsis is also characterized by a complex pathophysiology and usually affects patients with multiple comorbidities, thereby complicating sepsis-focused trials with significant heterogeneity.1 In this respect, the identification of biomarkers has become of paramount importance for the early detection, the classification, the therapeutic guidance, the prediction or the detection of complications, and the prognosis of sepsis.1,2Table 1 summarizes the most promising potential biomarkers of sepsis identified so far, as well as the nature of their function with regard to sepsis.1
Table 1Potential biomarkers of sepsis based on data reviewed by von Groote and Meersch-Dini1
| Biomarker(s) | Function of the biomarker(s) with regard to sepsis
|
|---|
| Early detection | Classification | Therapeutic guidance | Prediction or detection of complications | Prognosis |
|---|
| Adrenomedullin | | | + | | |
| Angiopoietin-1; Angiopoietin-2 | | | | + | |
| C-reactive protein | + | + | | | + |
| CD64 on neutrophils | + | | + | | + |
| Heparanase-1; Heparanase-2 | | | + | | |
| Human leukocyte antigen–DR isotype on antigen-presenting cells | | + | | + | + |
| IL-6 | + | + | | | |
| Interleukin-8 | | + | | | |
| Lipopolysaccharide-binding protein | | + | | | |
| Pathogen-associated molecular patterns | + | | | | |
| Pentraxin-3 | | | | + | + |
| Presepsin | + | + | + | | |
| Procalcitonin | | + | + | | |
| Soluble programmed death ligand 1 | | | + | + | |
| Syndecan-1 | | | + | + | |
| Thrombomodulin | | | | + | |
In a study published in this journal, Xiao et al.2 have undertaken a transcriptomic sequencing of mononuclear cells isolated from the peripheral blood samples of septic patients. The latter were divided into two groups based on the outcome of their hospitalization (i.e., survival or death), and the comparative analysis of the mononuclear cell transcriptomic sequences between these two groups has revealed a total of 475 differentially expressed genes (DEGs).2 After employing a Gene Ontology-based functional annotation and a Kyoto Encyclopedia of Genes and Genomes-based pathway enrichment analysis, Xiao et al.2 have revealed the DEGs exhibiting the most prominent differences within the pathways associated with metabolism. Amongst the identified genes, the relative expression of ENO1 (the gene encoding enolase-1; ENO-1) was found to be significantly upregulated in the survival group, and a subsequent quantitative real-time polymerase chain reaction-mediated verification was able to confirm this finding.2 Despite its limitations (small sample size and uneven groups), the study of Xiao et al.2 represents a valuable contribution to the ongoing biomarker mapping of sepsis, as it essentially suggests that ENO-1 could be a prognostic biomarker of sepsis. This is particularly important in view of the fact that prognosis is the least accommodated function by the identified potential biomarkers of sepsis (Table 1).
ENO-1 is a metalloenzyme that is mainly known for its involvement in glycolysis, where it catalyzes the interconversion of 2-phosphoglycerate to phosphoenolpyruvic acid. However, ENO-1 is also known to exhibit other activities that strongly depend on its intra- or extracellular localization.3 Qiao et al.4 have recently characterized ENO-1 as a “moonlighting protein”; a justified characterization when one considers that ENO-1 can also display an array of DNA-binding capacity-related activities (resulting in the regulation of gene expression) as well as a critical role in plasmin-mediated pericellular proteolysis (when ENO-1 is anchored on the cellular membrane).3 In fact, the cell surface-associated ENO-1 is known to play an important role in the regulation of pericellular proteolysis through the enhancement of plasmin formation; a role that has been well studied in the context of cancer cell migration and invasion.5
Interestingly, an increased expression of ENO-1 on the cell surface of blood monocytes and in alveolar space mononuclear cells of patients with pneumonia has been reported by Wygrecka et al.,6 while Xiao et al.2 recognize that the ability of ENO-1 to enhance monocytic invasion might be particularly relevant to the prognosis of sepsis. On the other hand, Lee et al.7 have found that apolipoprotein B (apoB) can act as a specific ligand to ENO-1 (with an affinity that exceeds that of plasminogen) in the synovial fluid of patients with rheumatoid arthritis, while when mononuclear cells from these patients were exposed in vitro to apoB for 24 h, they were found to overexpress pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6). These findings suggest that the activation of the cell surface-bound ENO-1 of mononuclear cells can aggravate inflammation in rheumatoid arthritis.7
The study of Xiao et al.2 is not the first to suggest a biomarker role for ENO-1. In fact, the expression levels of the latter have been found decreased in the serum of hepatitis B virus (HBV)-induced hepatic fibrosis patients as compared to those identified in the serum of HBV carriers,8 thereby indicating their potential utility as a diagnostic biomarker of hepatic fibrosis. A fundamental difference between a diagnostic and a prognostic biomarker is that the latter is more likely to inform the clinical management of complex and life-threatening diseases such as sepsis. In that respect, the readers of our journal will likely ask themselves a simple question: can we pharmacologically enhance the expression of ENO-1 so as to improve the prognosis of sepsis? Xiao et al.2 do not address this question. However, in a very interesting study by Zhu and McBride,9 TRP120 (an effector of Ehrlichia chaffeensis) has been shown to interact with ENO-1 and to increase the ubiquitination and the degradation of the latter. Moreover, the knockdown of ENO1 (through the use of small interfering RNAs) was able to disrupt the glycolytic flux of human monocytic leukemia cells (THP-1 cells), thereby affecting their pyruvate and lactate metabolism and promoting ehrlichial infection.9 Furthermore, in that same study, bortezomib (a proteasomal inhibitor) was shown to inhibit the TRP120-induced ENO-1 degradation.9 Not surprisingly, in an earlier study by Han et al.,10 bortezomib has been shown to reduce the expression of inflammatory cytokines (including those of TNF-α, IL-1β, and IL-6) in lipopolysaccharide-stimulated murine monocyte/macrophage-like RAW 264.7 cells, and to increase the survival in a murine model of sepsis involving cecal ligation and puncture-induced peritonitis.
Bortezomib (also known as PS-341 and being available as Velcade, Chemobort, and Bortecad) is a drug that has already been approved by the Food and Drug Administration for the treatment of multiple myeloma; therefore, the undertaking of preclinical studies should be prioritized in order to explore whether its repurposing for sepsis might be an option for the improvement of the prognosis of the latter.
Abbreviations
- apoB:
apolipoprotein B
- DEGs:
differentially expressed genes
- ENO-1:
enolase-1
- HBV:
hepatitis B virus
- IL-1β:
interleukin-1 beta
- IL-6:
interleukin-6
- TNF-α:
tumor necrosis factor alpha
Declarations
Acknowledgement
The author would like to thank Dr. Christina Elliott (Newcastle University) for her useful remarks on a draft version of this editorial.
Funding
None.
Conflict of interest
Dr. Apostolos Zarros has been an editorial board member of the Journal of Exploratory Research in Pharmacology from August 2021 to December 2022. The author has no other conflicts of interest related to this publication.