Research Progress of DcR3 in the Diagnosis and Treatment of Sepsis

Abstract

Decoy receptor 3 (DcR3), a soluble glycosylated protein in the tumor necrosis factor receptor superfamily, plays a role in tumor and inflammatory diseases. Sepsis is a life-threatening organ dysfunction caused by the dysregulation of the response to infection. Currently, no specific drug that can alleviate or even cure sepsis in a comprehensive and multi-level manner has been found. DcR3 is closely related to sepsis and considerably upregulated in the serum of those patients, and its upregulation is positively correlated with the severity of sepsis and can be a potential biomarker for diagnosis. DcR3 alone or in combination with other markers has shown promising results in the early diagnosis of sepsis. Furthermore, DcR3 is a multipotent immunomodulator that can bind FasL, LIGHT, and TL1A through decoy action, and block downstream apoptosis and inflammatory signaling. It also regulates T-cell and macrophage differentiation and modulates immune status through non-decoy action; therefore, DcR3 could be a potential drug for the treatment of sepsis. The application of DcR3 in the treatment of a mouse model of sepsis also achieved good efficacy. Here, we introduce and discuss the progress in, and suggest novel ideas for, research regarding DcR3 in the diagnosis and treatment of sepsis.

Keywords: biomarkers; decoy receptor 3; diagnosis; research progress; sepsis; treatment.

Figure 1

Exogenous pathogens promote DcR3 expression through the activation of NF-κB, PI3K-AKT, and other signaling pathways. LPS: lipopolysaccharide; PG: peptidoglycan; LTA: lipoteichoic acid; TLR4: toll-like receptor 4; TLR2: toll-like receptor 2; TRIF: tir domain-containing adaptor inducing interferon-beta; MYD88: myeloid differentiation factor 88; TAK1: transforming growth factor beta-activated kinase 1; TAB1/2: transforming growth factor beta-activated kinase 1 binding protein 1/2; IKKβ: IkappaB kinase β; IKKα: IkappaB kinase α; NEMO: nuclear factor kappaB essential modulator; PI3K: phosphoinositide 3 kinase; PDK1: 3-phosphoinositide-dependent protein kinase 1; AKT: protein kinase B; NF-κB: nuclear factor kappaB; DcR3: decoy receptor 3; P50: nuclear factor kappaB1; P65: nuclear factor kappa B2.

Figure 2

Biological functions of DcR3. (A) The decoy function of DcR3; (B) The non-decoy function of DcR3. LIGHT: tumor necrosis factor ligand superfamily member 14; TL1A: TNF-like molecule 1A; FasL: fas ligand; HVEM: herpesvirus entry mediator; LTβR: lymphotoxin beta receptor; DcR3: decoy receptor 3; DR3: death receptor 3; Fas: TNF superfamily receptor 6; CD44v3: cluster of differentiation 44 variant 3; ICAM-1: intercellular adhesion molecule 1; VCAM-1: vascular cell adhesion molecule-1; DC: dendritic cell; T: T lymphocytes; Th2: T-helper 2 cells.

Figure 3

Immune imbalance is the main feature of sepsis.

Figure 4

The developmental process of sepsis. DAMPs: damage-associated molecular patterns; PAMPs: pathogen-associated molecular patterns; PRRs: pattern recognition receptors; HMGB1: high mobility group box-1 protein; C3a: complement component 3a; C5a: complement component 5a; IL-1β: interleukin-1beta; IL-6: interleukin-6; TNF-α: tumor necrosis factor alpha; NO: nitrous oxide; IL-4: interleukin-4; IL-10: interleukin-10; IL-37: interleukin-37; TGF-β: transforming growth factor-beta; Treg: regulatory T-cells.

Figure 5

DcR3 inhibits cellular inflammation and reduces the apoptosis of immune cells. M0: M0-like macrophage; M1: M1-like macrophage; M2: M2-like macrophage; CD4+T: CD4 positive lymphocytes; Th1: T-helper 1 cells; Th2: T-helper 2 cells; IL-1β: interleukin-1beta; IL-6: interleukin-6; TNF-α: tumor necrosis factor alpha; NO: nitrous oxide; DcR3: decoy receptor 3; Fas: TNF superfamily receptor 6; FasL: fas ligand; LIGHT: tumor necrosis factor ligand superfamily member 14; LTβR: lymphotoxin-beta receptor; TL1A: TNF-like molecule 1A; DR3: death receptor 3.