Abstract
The N-terminal truncated form of a protein synthesis enzyme, tryptophanyl-tRNA synthetase (mini-WRS), is secreted as an angiostatic ligand. However, the secretion and function of the full-length WRS (FL-WRS) remain unknown. Here, we report that the FL-WRS, but not mini-WRS, is rapidly secreted upon pathogen infection to prime innate immunity. Blood levels of FL-WRS were increased in sepsis patients, but not in those with sterile inflammation. FL-WRS was secreted from monocytes and directly bound to macrophages via a toll-like receptor 4 (TLR4)–myeloid differentiation factor 2 (MD2) complex to induce phagocytosis and chemokine production. Administration of FL-WRS into Salmonella typhimurium-infected mice reduced the levels of bacteria and improved mouse survival, whereas its titration with the specific antibody aggravated the infection. The N-terminal 154-amino-acid eukaryote-specific peptide of WRS was sufficient to recapitulate FL-WRS activity and its interaction mode with TLR4–MD2 is now suggested. Based on these results, secretion of FL-WRS appears to work as a primary defence system against infection, acting before full activation of innate immunity.
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Acknowledgements
This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2010-0012505), Bio-Synergy/research Project (2014M3A9C4066465) and Global Frontier Project grants nos. NRF-M3A6A4-2010-0029785 and 2015M3A6A4065732 of the National Research Foundation funded by the Ministry of Science, ICT & Future Planning (MSIP) of Korea.
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Co-first authors Y.H.A. and S.P. performed the experiments and analysed the data. J.J.C., B.-K.P., K.H.R., E.K., S.A., K.-S.I., N.H.K., H.S., B.W.H., P.K., J.-Y.L. and Y.J. performed experiments. C.-H.L. and J.S.L. provided knockout animals. M.-L.C., S.-H.P., K.P., H.J.P., J.-H.L., J.-W.P. and J.W.H. provided sera and discussed clinical data. M.J. and S.K. designed the experiments, supervised the research and wrote the paper. All authors approved the final manuscript.
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Supplementary Information
Supplementary Figures 1–9, Supplementary Tables 1 and 2, legends for Supplementary Videos 1–6 (PDF 1599 kb)
Supplementary Video 1
Infiltration of neutrophil and monocyte/macraophage 30 min after PBS injection. (AVI 8931 kb)
Supplementary Video 2
Infiltration of neutrophil and monocyte/macraophage 4 hr after PBS injection. (AVI 11085 kb)
Supplementary Video 3
Infiltration of neutrophil and monocyte/macraophage 30 min after FL-WRS injection. (AVI 8204 kb)
Supplementary Video 4
Infiltration of neutrophil and monocyte/macraophage 4 hr after FL-WRS injection. (AVI 6213 kb)
Supplementary Video 5
Infiltration of neutrophil and monocyte/macraophage 30 min after mini-WRS 23 injection. (AVI 13234 kb)
Supplementary Video 6
Infiltration of neutrophil and monocyte/macraophage 4 hr after mini-WRS injection. (AVI 4830 kb)
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Ahn, Y., Park, S., Choi, J. et al. Secreted tryptophanyl-tRNA synthetase as a primary defence system against infection. Nat Microbiol 2, 16191 (2017). https://doi.org/10.1038/nmicrobiol.2016.191
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DOI: https://doi.org/10.1038/nmicrobiol.2016.191
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