Inhibition of TXNDC5 attenuates lipopolysaccharide-induced septic shock by altering inflammatory responses

Sepsis and its severe form, septic shock, represent the leading cause of death among hospitalized patients. Thioredoxin is a ubiquitous protein essential for cellular redox balance and its aberrant expression is associated with a wide spectrum of inflammation-related pathological conditions. The current study aimed to compare the expression of thioredoxin domain containing 5 (TXNDC5) in septic patients with or without septic shock and to explore the potential regulatory effects of TXNDC5 in sepsis. We analyzed the RNA expression data downloaded from the Gene Expression Omnibus database and measured the plasma level of TXNDC5 in septic patients. The results showed that TXNDC5 was upregulated in patients with septic shock compared to septic patients without shock or healthy controls. We further treated wild-type mice and cultured macrophages with lipopolysaccharide (LPS) and found that TXNDC5 was highly expressed in mice with LPS-induced sepsis and macrophages subjected to LPS stimulation compared to corresponding controls. Then a mouse strain with targeted depletion of Txndc5 was generated. Txndc5 depletion reduced inflammatory cytokine production and affected the recruitment of macrophages and neutrophils into the blood and peritoneum of mice challenged with LPS. Further analysis revealed that TXNDC5 inhibition alleviated LPS-induced sepsis by inhibiting the NF-κB signaling pathway. In summary, these findings suggested that the inhibition of TXNDC5 may be a potential approach to treat sepsis and related syndromes.