Blockage of S100A8/A9 ameliorates septic nephropathy in mice

Abstract

Septic acute kidney injury (AKI) is the commonest cause of complication of sepsis in intensive care units, but its pathophysiology remains unclear. Calprotectin (S100A8/A9), which is a damage-associated molecular patterns (DAMPs) molecule, exerts a critical role in modulating leukocyte recruitment and inflammatory response during various diseases. However, role of S100A8/A9 in septic AKI is largely unknown. In this research, Septic AKI was triggered by cecal ligation and puncture (CLP) operation in wild-type mice, which treated with or without an S100A9 inhibitor, Paquinimod (Paq, 10 mg/kg) that prevents S100A8/A9 to bind to Toll-like receptor 4 (TLR4). Renal function, pathological changes, cell death, and oxidative stress were evaluated. Our research indicated that the mRNA and protein expression of S100A9 are time-dependently elevated in the kidney following CLP. Moreover, the administration of Paq for 24 h significantly improved CLP-induced renal dysfunction and pathological alterations compared with vehicle treatment in mice. These beneficial effects were associated with the inhibition of CLP-triggered renal tubular epithelial cell apoptosis, inflammation, superoxide production, and mitochondrial dynamic imbalance. What’s more, we further confirmed the above findings by cell co-culture experiments. Our study demonstrates that S100A9 is a prominent protein to lead to septic AKI, and the selective inhibition of S100A9 could represent a new therapeutic approach which can treat septic AKI.

Integrated multi-omics and artificial intelligence to explore new neutrophils clusters and potential biomarkers in sepsis with experimental validation

“…This was consisted with our study, which is those specific neutrophils with CD177 Moreover, this new cluster of neutrophils were found absence in healthy individuals and newly released from the bone marrow (36). S100 family members S100A8 and S100A9 are cytoplasmic EFhand Ca2 + -binding proteins (37). A previous study verified that expressions of S100A8/A9 are elevated in blood cells of sepsis patients and S100A8/A9 showed high accuracy in sepsis diagnosis (38).…”

“…S100 family members S100A8 and S100A9 are cytoplasmic EF-hand Ca2 + -binding proteins ( 37 ). A previous study verified that expressions of S100A8/A9 are elevated in blood cells of sepsis patients and S100A8/A9 showed high accuracy in sepsis diagnosis ( 38 ).…”

“…In addition, NETs release S100A8/A9, which further promotes platelet pyroptosis ( 40 ). They combine to generate a heterodimer that is strongly expressed in active neutrophils ( 37 ). Moreover, S100A8/A9 was mostly enriched in damage-associated molecular patterns (DAMPs) ( 41 ).…”