Worldwide, sepsis has been regarded as one of the most life-threatening states and a major public health issue (Meyer and Prescott, 2024). Its updated definition, “organ dysfunction caused by a dysregulated host response to infection” (Sepsis-3), reflects an improved understanding of pathophysiology (Singer et al., 2016). Nevertheless, the clinical practices of sepsis and septic shock still face formidable challenges (de Backer et al., 2024), partly because the derived criteria based on the Sequential Organ Failure Assessment (SOFA) score may come at the expense of sensitivity, leading to delayed discrimination and intervention (Rhee and Klompas, 2017; Lambden et al., 2019). Early prognostic prediction is essential to assign risk profiles and establish treatment intensity, thereby modifying the outcome of patients (Povoa et al., 2023; Cajander et al., 2024).

Over the last decade, biomarkers have been implemented in sepsis to aid decision-making. A biomarker is a characteristic by which a specific physiological or pathological process can be recognized (Biomarkers Definitions Working G, 2001). Several analytes, including C-reactive protein (CRP), procalcitonin (PCT), and interleukin (IL)-6, turn into common markers of acute inflammatory response (Faix, 2013; Tziolos et al., 2015). Furthermore, novel candidates with different biological signatures are explored to help improve the effectiveness of existing assays (Pierrakos et al., 2020).

Decoy receptor 3 (DcR3), also named tumor necrosis factor (TNF) receptor superfamily member 6b, is a soluble receptor for three corresponding ligands involved in apoptosis and inflammation: Fas ligand (FasL), herpes virus entry mediator-L (LIGHT), and TNF-like molecule 1A (TL1A) (Pitti et al., 1998; Yu et al., 1999; Migone et al., 2002). In addition to its neutralizing ability, it directly regulates the differentiation and maturation of myeloid cells, biases the phenotype of helper T cells, inhibits the proliferation of B cells, and mediates the interaction of immune cells (Hsieh and Lin, 2017). The pleiotropic immunomodulator could be exclusively released by antigen-presenting cells (APCs), such as monocytes and dendritic cells (DCs), via the Toll-like receptor (TLR) 2/4-mediated mitogen-activated protein kinase (MAPK) pathway in response to bacterial antigens (Kim et al., 2004). A similar phenomenon was observed in treated human intestinal epithelial cells (IECs) as well (Kim et al., 2005). Increased DcR3 levels have been associated with the severity and outcome of acute respiratory distress syndrome (Chen et al., 2009), coronary artery disease (Chang et al., 2015), kidney diseases (Hung et al., 2012; Maruyama et al., 2016), and liver failure (Lin et al., 2019). In severe burns, non-survivors exhibited a fluctuating pattern of persistently high plasma DcR3 within 31-day monitoring (Min et al., 2021).

The potential of DcR3 as a biomarker for sepsis was also estimated. We previously reported a remarkable elevation of sera DcR3 that could distinguish patients meeting the Sepsis-2 criteria from non-infectious systemic inflammatory response syndrome (SIRS) and correlate with the Acute Physiology and Chronic Health Evaluation (APACHE) II score and PCT (Hou et al., 2012; Kim et al., 2012; Gao et al., 2018). Zhao et al (Zhao et al., 2018) suggested that when combined with PCT and soluble urokinase-type plasminogen activator receptor (suPAR), DcR3 enhanced the efficiency of sepsis diagnosis. Nevertheless, the clinical significance of biomarkers should be reinterpreted as the dedication in identifying sepsis has been shifted from an existing infection to a dysregulated inflammation. In this scenario, we conduct the present study to reappraise the prognostic value of DcR3 in patients suffering from sepsis and septic shock with the Sepsis-3 definitions.

The current study has supported DcR3 as an important prognostic factor in the early development of sepsis and septic shock. Proofs include the following: 1) the plasma DcR3 levels exhibited a significant disparity between survivors and non-survivors in patients with sepsis or septic shock; 2) the DcR3 levels were positively correlated with organ dysfunction as measured by the SOFA score; 3) among the four biomarkers, DcR3 was the only one independently associated with the 28-day mortality in both cohorts; and 4) the efficacy of DcR3 alone for outcome prediction was credible, which could be further improved when coupled with SOFA score.

It is another exploration on clinical significance of this molecule in sepsis, which has been allocated a fresh task according to the latest definitions. Rather than seeking conclusive microbiological evidence, practices in sepsis nowadays focus on the timely recognition of patients who may progress to a critical state (Singer et al., 2016). We herein adopted a stepwise and systematic statistical approach to visit the prognostic value of DcR3 and other parameters, providing more detailed information to help personalize management. Notably, the data enrolled in the analysis were mainly measured within the first 6 h of onset, with the belief that assigning risk profiles and predicting outcome as early as possible could be more beneficial (Povoa et al., 2023; Cajander et al., 2024). We previously reported two dynamic trends of DcR3 in individuals who died from sepsis, i.e., a sustained rise or an initial peak followed by a decline. Nevertheless, once the molecule reached a certain threshold, clinical outcomes would be poor regardless of the pattern (Gao et al., 2018).

The dysregulated immune responses and organ dysfunctions highlighted by the revised definition remain difficult to assess. Despite the validity to clinically characterize patients with sepsis, the SOFA score is less sensitive and is a complicated algorithm (Rhee and Klompas, 2017; Lambden et al., 2019). Analysis from the Medical Information Mart for Intensive Care-III (MIMIC-III) database showed that the definitions of Sepsis-3 may have narrowed the sepsis population in comparison with Sepsis-1, leading to false negatives. Among patients who did not satisfy the new diagnostic criteria, the fatality rate was over 6.0% (Fang et al., 2018). In a cohort with severe Gram-negative infections, the earliest time point for change in SOFA score to determine prognosis was the 7th day after sepsis, implying a dullness in the recognition of illness (Karakike et al., 2019). With a well-established ELISA, soluble DcR3 could be efficiently and promptly determined across a variety of human biological fluids, proving its broad clinical applicability (Chen et al., 2004). The rising concentration was not only linked to the occurrence and progression of the acute inflammations previously enumerated but could also be seen in chronic illnesses and tumors (Wu et al., 2003; Connor and Felder, 2008; Aiba et al., 2014; Xiu et al., 2015). In specific contexts, its levels may serve as a basis for distinguishing different pathophysiological states. During the Sepsis-2 era, we have serially reported the ability of a remarkable elevation of serum DcR3 to discriminate sepsis from SIRS, as well as its correlation with the severity of infection (Hou et al., 2012; Kim et al., 2012; Gao et al., 2018). In this study, using the marker alone could achieve a similar AUC value to that of using the scoring system for the prediction of 28-day mortality, raising its benefits in clinical settings. Moreover, DcR3 levels appeared most correlated to SOFA scores, hinting at a potential relationship with the advancement of organ dysfunction, as revealed in other studies (Chen et al., 2009).

Compared with the three other important inflammatory biomarkers (i.e., CRP, PCT, and IL-6), DcR3 showed a stronger capacity on outcome prediction, which is consistent with our recent observations from in-vitro experiments (unpublished data). When monocytes were stimulated with varying concentrations of lipopolysaccharide (LPS), the levels of most inflammatory factors demonstrated a significant increase under mild conditions, whereas DcR3 only showed an appropriate response to intense stimulation, suggesting it as a more suitable biomarker for sepsis. A proper comprehension of the unique biological effects of this molecule may help interpret the results. Similar to most acute-phase reactants or proinflammatory cytokines, DcR3 can be triggered by pathogens or insults, thus becoming detectable in circulation. However, unlike them, it tends to attenuate inflammation and facilitate tissue repair by suppressing the release of cytotoxic mediators, preventing apoptosis and inducing differentiation (Liang et al., 2015; Su et al., 2024). From a physiological perspective, the upregulation of DcR3 represents a negative feedback mechanism of the host to maintain a moderate immune response and return to homeostasis. However, the product may not be sufficient to eliminate hyperinflammation in a pathological setting (Min et al., 2021). Therefore, the detected level of DcR3 can be regarded as a sign for the dysregulated degree of response and distinguish protective inflammation from pathological cytokine storm (Fajgenbaum and June, 2020). The aforementioned hypothesis plausibly elucidates the paradox that supplementation of DcR3 may serve as a promising immunotherapeutic agent for numerous inflammatory diseases including sepsis, while its endogenous counterpart functions as a biomarker indicative of organ dysfunction and dismal outcomes (Su et al., 2023). The gap between the intensity of inflammation and the amount of molecules involved in the reaction appears to be a crucial component affecting the fate of the host.

In particular, DcR3 was the only biomarker independently associated with 28-day mortality of patients with septic shock and gave the greatest AUC for predicting death. We speculated that the results may be related to the extensive and severe damage of the endothelium, a key element in septic shock pathophysiology. Endothelial dysfunction caused by the innate immune response to infection would bring about impaired microvascular perfusion, inadequate tissue oxygenation, and abnormal cell metabolism and contribute to a decrease in venous return and hence sepsis-induced hypotension. In addition, endothelial alteration is also implicated in the inflammatory activation and coagulation processes leading to the amplification of septic response and development of organ dysfunction (de Backer et al., 2021; Bakker et al., 2022). It has been proven that DcR3 could be upregulated at both the mRNA and protein levels following treatment with different microbial toxins in human umbilical vein endothelial cells (HUVECs) (Yoo et al., 2012; Hou et al., 2018), and interestingly, its ligand TL1A seems to be exclusively expressed in HUVECs rather than human aortic endothelial cells (HAECs), acting as a potent inhibitor to induce endothelial apoptosis and suppress angiogenesis (Yang et al., 2004). This may partially explain the predominance of microcirculatory injury on the venular side during septic shock, but further supportive studies are needed. Recently, we reported a profound elevation of DcR3 in severe burn shock pathologically characterized by massive endothelial damage and capillary leakage. The increase was pronounced by a co-infected state and was associated with the death of subjects that fulfilled the diagnostic criteria for septic shock (Min et al., 2021). Together with previous studies, our findings show that DcR3 can become an expected predictor for the outcome of septic shock.

It should be acknowledged that DcR3 failed to discriminate among sepsis cases caused by diverse pathogens, and none of the biomarkers in our study presented sufficiently convincing predictive power for prognosis. Due to the multifaceted nature of the host response to infection, it is difficult to determine the contribution of different causative microorganisms to DcR3 induction despite different mechanisms (Kim et al., 2004). Likewise, in light of the complicated pathobiology, no single indicator hitherto has been reliable enough for diagnosing sepsis or predicting outcomes. The integration of laboratory parameters with clinical data can provide more specific pathophysiological information, which is promising to overcome the obstacles (Yang et al., 2016; Mearelli et al., 2018). Our results indicate that paired with SOFA score, DcR3 has a good synergistic effect in predicting the prognosis of sepsis and can be used as a good complementary tool with application prospects. Yet, it was not combined with other biomarkers because of their weak predictive capabilities and possible intrinsic relationship with DcR3. The combination of multiple markers has not constantly outperformed an individual one (Parlato et al., 2018).

Patients with coexisting tumors were excluded from our study, given the controversy over whether the presence of tumors affects the level of DcR3 responses in an inflammatory state (Thompson and Connor, 2019). Other underlying diseases were also adjusted in multivariate regression analyses to minimize their impact on outcomes.

The Sepsis-3 definition requires more precise outcome prediction and risk stratification. The current study discloses the potential of DcR3 as a prognostic biomarker in the early development of sepsis and septic shock by predicting 28-day mortality. Nevertheless, further validation studies are warranted before it can be routinely utilized in the clinical assessment of critically ill patients.