IRAK1 as a shunt in multi-ligand signaling through Toll-like receptors

Authors

• SJ Vayttaden
• M Smelkinson
• Z Benet
• RA Gottschalk
• RN Germain
• MK Meier-Schellersheim
• RR Varma
• IDC Fraser

Abstract

During an infection, macrophages encounter multiple PAMPs and a coherent immune response likely involves crosstalk between various PRR pathways. During large-scale profiling of pathway crosstalk, we have identified patterns of synergistic and antagonistic signaling outcomes for combinations of TLR ligands. Stimulation of murine macrophages with a combination of TLR2 and TLR4 ligands leads to a pattern of mostly suppressed downstream phosphoprotein activation and transcriptional output, but with synergistic activation of select readouts. We discovered that IRAK1 forms clusters in the cytoplasm specifically upon dual TLR stimulation. Cells high in IRAK1 clusters have lower MAPK activation and nuclear staining of transcription factors like pATF2, but higher LC3 puncta (autophagosome marker) and ASC nucleation (inflammasome marker). IRAK1 clusters also colocalize with the downstream TLR signal propagators TRAF6, TAK1 and TAB2. Furthermore, in IRAK1KO cells, phosphoprotein and cytokine responses to dual TLR ligands are higher than in WT cells. We conclude from this data that, IRAK1 may be an important attenuator of signaling in response to combined TLR ligands, and that IRAK1-dependent sequestration of key TLR signal propagators into the clusters might be a mechanism for limiting signaling flux. Furthermore, the colocalization of clusters with inflammasome components suggests IRAK1 might act as a shunt, rerouting signals between PRR pathways under specific conditions. This may allow the cell to diversify the immune response to complex microbial signals through priming of multiple host response pathways, and may be an important mechanism for improving the quality of the immune response during a severe infection.

Scientific Focus Area: Immunology

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