The nitrone spin trap DMPO binds to toll-like receptor-2-TIR-BB-loop domain and dampens downstream inflammatory signaling.

MUÑOZ MD,; GUTIERREZ LJ, ; DELIGNAT S,; RUSSICK J, ; LACROIX-DESMAZES S,; ENRIZ RD, ; RAMIREZ DC; GOMEZ MEJIBA SE,CO-CORRESPONDING AUTHOR

BBA Molecular Basis Diseases

ELSEVIER SCIENCE

Año: 2019

1437-4315

The nitrone spin trap 5,5‑dimethyl‑1‑pyrroline N‑oxide (DMPO) dampens endotoxin-induced and TLR4-driven priming of macrophages, but the mechanism remains unknown. The available information suggests a direct binding of DMPO to the TIR domain, which is shared between TLRs. However, TLR2-TIR domain is the only TLR that have been crystallized. Our in silico data show that DMPO binds to four specific residues in the BB-loop within the TLR2-TIR domain. Our functional analysis using hTLR2.6-expressing HEKs cells showed that DMPO can block zymosan-triggered-TLR2-mediated NF-κB activation. However, DMPO did not affect the overall TLR2-MyD88 protein-protein interaction. DMPO binds to the BB-loop in the TIR-domain and dampens downstream signaling without affecting the overall TIR-MyD88 interaction. These data encourage the use of DMPO-derivatives as potential mechanism-based inhibitors of TLR-triggered inflammation.