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울산대학교 의과대학 서울아산병원

EMBO Mol. Med., 14 December 2023 | https://doi.org/10.1038/s44321-023-00004-y Highly secreted tryptophanyl tRNA synthetase 1 as a potential theranostic target for hypercytokinemic severe sepsis

Yoon Tae Kim ^1,16, Jin Won Huh ^2,16, Yun Hui Choi ³, Hee Kyeong Yoon ³, Tram TT Nguyen ³, Eunho Chun ¹, Geunyeol Jeong ¹, Sunyoung Park ⁴, Sungwoo Ahn ⁵, Won-Kyu Lee ⁶, Young-Woock Noh ⁶, Kyoung Sun Lee ⁷, Hee-Sung Ahn ⁸, Cheolju Lee ⁹, Sang Min Lee ¹⁰, Kyung Su Kim ¹¹, Gil Joon Suh ¹², Kyeongman Jeon¹³, Sunghoon Kim ¹⁴& Mirim Jin ^1,3,4,15,*

¹Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, Republic of Korea.
²Department of Pulmonary and Critical Care Medicine, Asan MedicalCenter, University of Ulsan College of Medicine, Seoul, Republic of Korea.
³R&D Center, MirimGENE, Incheon, Republic of Korea.
⁴Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea.
⁵Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada.
⁶New Drug Development Center, Osong Medical Innovation Foundation, Cheongju, Republic of Korea.
⁷Non-Clinical Evaluation Center, Osong Medical Innovation Foundation, Cheongju, Republic of Korea.
⁸Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.
⁹Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea.
¹⁰Department of Internal Medicine, Gil Medical Center, College of Medicine, Gachon University, Incheon, Republic of Korea.
¹¹Department of Emergency Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
¹²Department of Emergency Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
¹³Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
¹⁴Medicinal Bioconvergence Research Center, Institute for Artificial Intelligence and Biomedical Research, The interdisciplinary graduate program in integrative biotechnology, College of Pharmacy & College of Medicine, Gangnam Severance Hospital, Yonsei University, Incheon, Republic of Korea.
¹⁵Department of Microbiology, College of Medicine, Gachon University, Incheon, Republic of Korea.
¹⁶These authors contributed equally: Yoon Tae Kim, Jin Won Huh

^*Corresponding author: correspondence to Mirim Jin

Abstract

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.

논문정보

형식Research article
게재일2023년 12월 (BRIC 등록일 2023-12-18)
연구진국내(교신)+국외 연구진
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