Whey Acidic Protein/Four-Disulfide Core Domain 21 Regulate Sepsis Pathogenesis in a Mouse Model and a Macrophage Cell Line via the Stat3/Toll-Like Receptor 4 (TLR4) Signaling Pathway

Abstract

BackgroundWhey acidic protein/four-disulfide core domain 21 (Wfdc21), also known as Lnc-DC, it has been reported to be correlated with immune response. However, the role of Wfdc21 in the pathogenesis of sepsis is still unknown. In the present study, we aimed to investigate the role of Wfdc21 in the pathogenesis of sepsis.Material/MethodsThe cecal ligation and puncture (CLP)-induced sepsis model was established in Balb/c mice. Animals were euthanized 4, 8, 16, or 24 h after CLP. The glycogen distribution in the kidney and liver was checked by Periodic acid-Schiff (PAS) staining. Changes in the serum interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) concentrations were monitored with ELISA, and Wdfc21 expression was determined by qPCR. Mouse macrophage-like RAW264.7 cells were treated with different doses of lipopolysaccharide (LPS) from Escherichia coli to mimic sepsis in vitro. Western blot analysis was performed to confirm whether LPS-induced in vitro sepsis was correlated with the involvement of the Stat3/TLR4 signaling pathway. In addition, RAW 264.7 cells were infected with lentiviruses containing Wfdc21 shRNA to further confirm the role of Wfdc21 in the pathogenesis of sepsis.ResultsWe found that Wfdc21 level was elevated in the CLP-induced animal model and LPS-treated RAW264.7 cells. Furthermore, the downregulation of Wfdc21 modulated the concentration of pro-inflammatory factors in LPS-treated macrophages, such as IL-1β and TNF-α, in LPS-treated macrophages. This regulatory effect was mediated through the Stat3/TLR4 signaling pathway, since Wfdc21 can regulate p-Stat3 and TLR4 levels in LPS-treated macrophages.ConclusionsWfdc21 plays a critical role in the pathogenesis of sepsis and may provide a therapeutic target for sepsis treatment.

Extracellular Histone H3 Induces Pyroptosis During Sepsis and May Act Through NOD2 and VSIG4/NLRP3 Pathways

“…Despite rising medical standards, sepsis still lacks effective treatments. Lipopolysaccharide (LPS) is the main stimulus to induce sepsis, which can activate inflammatory cells through multiple pathways such as toll-like receptor 4 (TLR4) and promote the expression of inflammatory factors (Hayashi and Suzuki, 2015;Xie et al, 2018). Sepsis is closely related to the cascade of cytokines and cytokine storms triggered by pathogen-associated molecular patterns (PAMPs) (Cavaillon, 2018).…”

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“…FOXP1 has protein-protein interaction with NFAT1 to enhance breast cancer cell motility [18] and FOXP2 is essential in growth arrest of 143 osteosarcoma cells via p21 activation [19]. Also, FOXP3 is associated with IL-17 [20], RUNX1 [21], STAT3 [22], NF-κB [23], FOXO3 [24] and other cofactors such as EOS ( Ikzf4 ) [25], interferon regulatory factor 4 (IRF4) [26], special AT-rich sequence-binding protein-1 (SATB1) [25, 27] and GATA1, while FOXP4 is closely associated with miR 4316 in breast cancer cells [28], miR 491–5p in osteosarcoma [29] and miR 338-3p in hepatocellular carcinoma [30].…”

Long Noncoding RNA: Regulatory Mechanisms and Therapeutic Potential in Sepsis

“…Another lncRNA that participates in sepsis via TLR4 signaling pathway is acidic protein/four-disulfide core domain 21 (Wfdc21), also known as lncRNA DC, whose expression level was elevated in the cecal ligation and perforation (CLP)-induced animal model as well as LPS-induced macrophages. At the molecular level, the downregulation of Wfdc21 modulated the concentration of pro-inflammatory factors, mediated through the Stat3/TLR4 signaling pathway, in LPS-induced macrophages ( Xie et al., 2018 ). Similarly, a study conducted by Wang et al.…”