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

Biomolecules. 2020 Sep 6;10(9):1283. doi: 10.3390/biom10091283.


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.

Keywords: MyD88; TREM-1; TRIF; innate immunity; tryptophanyl-tRNA synthetase 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Adaptor Proteins, Vesicular Transport / metabolism
  • Animals
  • Cell Line
  • Chemokines / metabolism
  • Cytokines / metabolism
  • Humans
  • Inflammation / metabolism
  • Leukocytes, Mononuclear / metabolism
  • Mice
  • Myeloid Differentiation Factor 88 / metabolism
  • Signal Transduction / physiology
  • Syk Kinase / metabolism
  • Toll-Like Receptor 2 / metabolism*
  • Toll-Like Receptor 4 / metabolism*
  • Triggering Receptor Expressed on Myeloid Cells-1 / biosynthesis
  • Triggering Receptor Expressed on Myeloid Cells-1 / metabolism*
  • Tryptophan-tRNA Ligase / physiology*


  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • Chemokines
  • Cytokines
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • TICAM-1 protein, mouse
  • TLR2 protein, human
  • TLR4 protein, human
  • TREM1 protein, human
  • TREM1 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Triggering Receptor Expressed on Myeloid Cells-1
  • Tyrobp protein, mouse
  • Syk Kinase
  • Syk protein, mouse
  • Tryptophan-tRNA Ligase
  • WARS1 protein, human