The nitrone spin trap 5,5‑dimethyl‑1‑pyrroline N‑oxide binds to toll-like receptor-2-TIR-BB-loop domain and dampens downstream inflammatory signaling

MUÑOZ, MARCOS D.; GUTIERREZ, LUCAS J.; DELIGNAT, SANDRINE; RUSSICK, JULES; GOMEZ MEJIBA, SANDRA E.; LACROIX-DESMAZES, SEBASTIEN; ENRIZ, RICARDO D.; RAMIREZ, DARIO C.

BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR BASIS OF DISEASE

ELSEVIER SCIENCE BV

Año: 2019 vol. 1865 p. 1152 - 1159

0925-4439

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.