Highly secreted tryptophanyl tRNA synthetase 1 as a potential theranostic target for hypercytokinemic severe sepsis.
Yoon Tae KimJin Won HuhYun Hui ChoiHee Kyeong YoonTram Tt NguyenEunho ChunGeunyeol JeongSunyoung ParkSungwoo AhnWon Kyu LeeYoung-Woock NohKyoung Sun LeeHee-Sung AhnCheolju LeeSang Min LeeKyung Su KimGil Joon SuhKyeongman JeonSunghoon KimMirim JinPublished in: EMBO molecular medicine (2023)
Despite intensive clinical and scientific efforts, the mortality rate of sepsis remains high due to the lack of precise biomarkers for patient stratification and therapeutic guidance. Secreted human tryptophanyl-tRNA synthetase 1 (WARS1), an endogenous ligand for Toll-like receptor (TLR) 2 and TLR4 against infection, activates the genes that signify the hyperinflammatory sepsis phenotype. High plasma WARS1 levels stratified the early death of critically ill patients with sepsis, along with elevated levels of cytokines, chemokines, and lactate, as well as increased numbers of absolute neutrophils and monocytes, and higher Sequential Organ Failure Assessment (SOFA) scores. These symptoms were recapitulated in severely ill septic mice with hypercytokinemia. Further, injection of WARS1 into mildly septic mice worsened morbidity and mortality. We created an anti-human WARS1-neutralizing antibody that suppresses proinflammatory cytokine expression in marmosets with endotoxemia. Administration of this antibody into severe septic mice attenuated cytokine storm, organ failure, and early mortality. With antibiotics, the antibody almost completely prevented fatalities. These data imply that blood-circulating WARS1-guided anti-WARS1 therapy may provide a novel theranostic strategy for life-threatening systemic hyperinflammatory sepsis.
Keyphrases
- acute kidney injury
- toll like receptor
- septic shock
- intensive care unit
- inflammatory response
- endothelial cells
- immune response
- nuclear factor
- photodynamic therapy
- poor prognosis
- early onset
- stem cells
- adipose tissue
- case report
- signaling pathway
- genome wide
- mesenchymal stem cells
- dendritic cells
- risk factors
- climate change
- deep learning
- cardiovascular disease
- bone marrow
- depressive symptoms
- dengue virus
- pluripotent stem cells
- fluorescence imaging
- long non coding rna
- physical activity
- risk assessment
- replacement therapy
- data analysis