Cargando…
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...
Autores principales: | , , , , , |
---|---|
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 |
_version_ | 1783595871846268928 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7565148 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT nguyentramtt tryptophanyltrnasynthetase1signalsactivatetrem1viatlr2andtlr4 AT yoonheekyeong tryptophanyltrnasynthetase1signalsactivatetrem1viatlr2andtlr4 AT kimyoontae tryptophanyltrnasynthetase1signalsactivatetrem1viatlr2andtlr4 AT choiyunhui tryptophanyltrnasynthetase1signalsactivatetrem1viatlr2andtlr4 AT leewonkyu tryptophanyltrnasynthetase1signalsactivatetrem1viatlr2andtlr4 AT jinmirim tryptophanyltrnasynthetase1signalsactivatetrem1viatlr2andtlr4 |