Control of Overly Secreted Tryptophanyl tRNA Synthetase Attenuates Sepsis Severity in a Porcine Model.

Abstract

Sepsis is a leading cause of mortality in hospitals with a lack of reliable biomarkers and specialized therapeutics. Recently, highly secreted tryptophanyl-tRNA synthetase 1 (WARS1), an endogenous ligand for Toll-like receptor (TLR) 2 and TLR4, was found to be a potential theranostic target for hypercytokinemic severe sepsis. In this study, using the minipig sepsis model inoculated with cecum slurry, we demonstrated that increases in WARS1 levels were associated with severity of sepsis and showed strong correlations with RBC count and the levels of HGB, HCT, EPO, lactate, and PLT count in the acute phase of sepsis. Further, administration of the WARS1 neutralizing antibody to the septic minipigs inhibited the increase in the overall SOFA score with a significantly lower P/F ratio, which was accompanied by the suppression of proinflammatory cytokine and chemokine expressions as well as EPO production, a decrease in AST and ALT levels, and inflammatory immune cell infiltration in the lung. Taken together, these findings provide a novel insight into the pathophysiology of acute phase of sepsis and suggest the clinical application of WARS1 neutralizing therapeutics in the treatment of sepsis.