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Tryptophanyl-tRNA Synthetase 1 Signals Activate TREM-1 via TLR2 and TLR4

Tryptophanyl-tRNA synthetase 1 (WARS1) is an endogenous ligand of mammalian Toll-like receptors (TLR) 2 and TLR4. Microarray data, using mRNA from WARS1-treated human peripheral blood mononuclear cells (PBMCs), had indicated WARS1 to mainly activate innate inflammatory responses. However, exact mole...

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Autores principales: Nguyen, Tram T. T., Yoon, Hee Kyeong, Kim, Yoon Tae, Choi, Yun Hui, Lee, Won-Kyu, Jin, Mirim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565148/
https://www.ncbi.nlm.nih.gov/pubmed/32899943
http://dx.doi.org/10.3390/biom10091283
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author Nguyen, Tram T. T.
Yoon, Hee Kyeong
Kim, Yoon Tae
Choi, Yun Hui
Lee, Won-Kyu
Jin, Mirim
author_facet Nguyen, Tram T. T.
Yoon, Hee Kyeong
Kim, Yoon Tae
Choi, Yun Hui
Lee, Won-Kyu
Jin, Mirim
author_sort Nguyen, Tram T. T.
collection PubMed
description Tryptophanyl-tRNA synthetase 1 (WARS1) is an endogenous ligand of mammalian Toll-like receptors (TLR) 2 and TLR4. Microarray data, using mRNA from WARS1-treated human peripheral blood mononuclear cells (PBMCs), had indicated WARS1 to mainly activate innate inflammatory responses. However, exact molecular mechanism remains to be understood. The triggering receptor expressed on myeloid cells (TREM)-1 is an amplifier of pro-inflammatory processes. We found WARS1 to significantly activate TREM-1 at both mRNA and protein levels, along with its cell surface expression and secretion in macrophages. WARS1 stimulated TREM-1 production via TLR2 and TLR4, mediated by both MyD88 and TRIF, since targeted deletion of TLR4, TLR2, MyD88, and TRIF mostly abrogated TREM-1 activation. Furthermore, WARS1 promoted TREM-1 downstream phosphorylation of DAP12, Syk, and AKT. Knockdown of TREM-1 and inhibition of Syk kinase significantly suppressed the activation of inflammatory signaling loop from MyD88 and TRIF, leading to p38 MAPK, ERK, and NF-κB inactivation. Finally, MyD88, TRIF, and TREM-1 signaling pathways were shown to be cooperatively involved in WARS1-triggered massive production of IL-6, TNF-α, IFN-β, MIP-1α, MCP-1, and CXCL2, where activation of Syk kinase was crucial. Taken together, our data provided a new insight into WARS1′s strategy to amplify innate inflammatory responses via TREM-1.
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spelling pubmed-75651482020-10-26 Tryptophanyl-tRNA Synthetase 1 Signals Activate TREM-1 via TLR2 and TLR4 Nguyen, Tram T. T. Yoon, Hee Kyeong Kim, Yoon Tae Choi, Yun Hui Lee, Won-Kyu Jin, Mirim Biomolecules Article Tryptophanyl-tRNA synthetase 1 (WARS1) is an endogenous ligand of mammalian Toll-like receptors (TLR) 2 and TLR4. Microarray data, using mRNA from WARS1-treated human peripheral blood mononuclear cells (PBMCs), had indicated WARS1 to mainly activate innate inflammatory responses. However, exact molecular mechanism remains to be understood. The triggering receptor expressed on myeloid cells (TREM)-1 is an amplifier of pro-inflammatory processes. We found WARS1 to significantly activate TREM-1 at both mRNA and protein levels, along with its cell surface expression and secretion in macrophages. WARS1 stimulated TREM-1 production via TLR2 and TLR4, mediated by both MyD88 and TRIF, since targeted deletion of TLR4, TLR2, MyD88, and TRIF mostly abrogated TREM-1 activation. Furthermore, WARS1 promoted TREM-1 downstream phosphorylation of DAP12, Syk, and AKT. Knockdown of TREM-1 and inhibition of Syk kinase significantly suppressed the activation of inflammatory signaling loop from MyD88 and TRIF, leading to p38 MAPK, ERK, and NF-κB inactivation. Finally, MyD88, TRIF, and TREM-1 signaling pathways were shown to be cooperatively involved in WARS1-triggered massive production of IL-6, TNF-α, IFN-β, MIP-1α, MCP-1, and CXCL2, where activation of Syk kinase was crucial. Taken together, our data provided a new insight into WARS1′s strategy to amplify innate inflammatory responses via TREM-1. MDPI 2020-09-06 /pmc/articles/PMC7565148/ /pubmed/32899943 http://dx.doi.org/10.3390/biom10091283 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Nguyen, Tram T. T.
Yoon, Hee Kyeong
Kim, Yoon Tae
Choi, Yun Hui
Lee, Won-Kyu
Jin, Mirim
Tryptophanyl-tRNA Synthetase 1 Signals Activate TREM-1 via TLR2 and TLR4
title Tryptophanyl-tRNA Synthetase 1 Signals Activate TREM-1 via TLR2 and TLR4
title_full Tryptophanyl-tRNA Synthetase 1 Signals Activate TREM-1 via TLR2 and TLR4
title_fullStr Tryptophanyl-tRNA Synthetase 1 Signals Activate TREM-1 via TLR2 and TLR4
title_full_unstemmed Tryptophanyl-tRNA Synthetase 1 Signals Activate TREM-1 via TLR2 and TLR4
title_short Tryptophanyl-tRNA Synthetase 1 Signals Activate TREM-1 via TLR2 and TLR4
title_sort tryptophanyl-trna synthetase 1 signals activate trem-1 via tlr2 and tlr4
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565148/
https://www.ncbi.nlm.nih.gov/pubmed/32899943
http://dx.doi.org/10.3390/biom10091283
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