Highly secreted tryptophanyl tRNA synthetase 1 as a potential theranostic target for hypercytokinemic severe sepsis
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2023-12-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s44321-023-00004-y |
| _version_ | 1797273609498001408 |
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| author | Yoon Tae Kim Jin Won Huh Yun Hui Choi Hee Kyeong Yoon Tram TT Nguyen Eunho Chun Geunyeol Jeong Sunyoung Park Sungwoo Ahn Won-Kyu Lee Young-Woock Noh Kyoung Sun Lee Hee-Sung Ahn Cheolju Lee Sang Min Lee Kyung Su Kim Gil Joon Suh Kyeongman Jeon Sunghoon Kim Mirim Jin |
| author_facet | Yoon Tae Kim Jin Won Huh Yun Hui Choi Hee Kyeong Yoon Tram TT Nguyen Eunho Chun Geunyeol Jeong Sunyoung Park Sungwoo Ahn Won-Kyu Lee Young-Woock Noh Kyoung Sun Lee Hee-Sung Ahn Cheolju Lee Sang Min Lee Kyung Su Kim Gil Joon Suh Kyeongman Jeon Sunghoon Kim Mirim Jin |
| author_sort | Yoon Tae Kim |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T14:46:51Z |
| format | Article |
| id | doaj.art-95aa08b534b248e8b6128193ae67ae34 |
| institution | Directory Open Access Journal |
| issn | 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T14:46:51Z |
| publishDate | 2023-12-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-95aa08b534b248e8b6128193ae67ae342024-03-05T19:55:56ZengSpringer NatureEMBO Molecular Medicine1757-46842023-12-01161406310.1038/s44321-023-00004-yHighly secreted tryptophanyl tRNA synthetase 1 as a potential theranostic target for hypercytokinemic severe sepsisYoon Tae Kim0Jin Won Huh1Yun Hui Choi2Hee Kyeong Yoon3Tram TT Nguyen4Eunho Chun5Geunyeol Jeong6Sunyoung Park7Sungwoo Ahn8Won-Kyu Lee9Young-Woock Noh10Kyoung Sun Lee11Hee-Sung Ahn12Cheolju Lee13Sang Min Lee14Kyung Su Kim15Gil Joon Suh16Kyeongman Jeon17Sunghoon Kim18Mirim Jin19Department of Health Sciences and Technology, GAIHST, Gachon UniversityDepartment of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of MedicineR&D Center, MirimGENER&D Center, MirimGENER&D Center, MirimGENEDepartment of Health Sciences and Technology, GAIHST, Gachon UniversityDepartment of Health Sciences and Technology, GAIHST, Gachon UniversityLee Gil Ya Cancer and Diabetes Institute, Gachon UniversityArnie Charbonneau Cancer Institute, University of CalgaryNew Drug Development Center, Osong Medical Innovation FoundationNew Drug Development Center, Osong Medical Innovation FoundationNon-Clinical Evaluation Center, Osong Medical Innovation FoundationConvergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical CenterChemical & Biological Integrative Research Center, Korea Institute of Science and TechnologyDepartment of Internal Medicine, Gil Medical Center, College of Medicine, Gachon UniversityDepartment of Emergency Medicine, Seoul National University HospitalDepartment of Emergency Medicine, Seoul National University College of MedicineDivision of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of MedicineMedicinal 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 UniversityDepartment of Health Sciences and Technology, GAIHST, Gachon UniversityAbstract 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.https://doi.org/10.1038/s44321-023-00004-ySepsisTheranosticsTryptophanyl-tRNA Synthetase (WARS1)HypercytokinemiaAnti-WARS1 Antibody |
| spellingShingle | Yoon Tae Kim Jin Won Huh Yun Hui Choi Hee Kyeong Yoon Tram TT Nguyen Eunho Chun Geunyeol Jeong Sunyoung Park Sungwoo Ahn Won-Kyu Lee Young-Woock Noh Kyoung Sun Lee Hee-Sung Ahn Cheolju Lee Sang Min Lee Kyung Su Kim Gil Joon Suh Kyeongman Jeon Sunghoon Kim Mirim Jin Highly secreted tryptophanyl tRNA synthetase 1 as a potential theranostic target for hypercytokinemic severe sepsis EMBO Molecular Medicine Sepsis Theranostics Tryptophanyl-tRNA Synthetase (WARS1) Hypercytokinemia Anti-WARS1 Antibody |
| title | Highly secreted tryptophanyl tRNA synthetase 1 as a potential theranostic target for hypercytokinemic severe sepsis |
| title_full | Highly secreted tryptophanyl tRNA synthetase 1 as a potential theranostic target for hypercytokinemic severe sepsis |
| title_fullStr | Highly secreted tryptophanyl tRNA synthetase 1 as a potential theranostic target for hypercytokinemic severe sepsis |
| title_full_unstemmed | Highly secreted tryptophanyl tRNA synthetase 1 as a potential theranostic target for hypercytokinemic severe sepsis |
| title_short | Highly secreted tryptophanyl tRNA synthetase 1 as a potential theranostic target for hypercytokinemic severe sepsis |
| title_sort | highly secreted tryptophanyl trna synthetase 1 as a potential theranostic target for hypercytokinemic severe sepsis |
| topic | Sepsis Theranostics Tryptophanyl-tRNA Synthetase (WARS1) Hypercytokinemia Anti-WARS1 Antibody |
| url | https://doi.org/10.1038/s44321-023-00004-y |
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