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

MUNOZ, MD; GUTIERREZ, L; DELIGNAT, S; RUSSICK, J; GOMEZ MEJIBA, SE; LAACROIX-DESMAZES, S; ENRIZ, RD; RAMIREZ, DC

BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR BASIS OF DISEASE

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2018

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-kb 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.