The Nitrone 5,5-dimethyl-1-pyrroline N-oxide is an Antagonist of Lipopolysaccharide Triggered TLR-signaling

RAMIREZ DARIO; MUÑOZ M; GUTIERREZ L; ENRIZ D; GOMEZ-MEJIBA SANDRA; AGUILAR AR; DI SCIULLO, MARÍA PAULA; CLAVELES CASAS, FN

Las Vegas

Congreso; The Society for Redox Biology and Medicine´s 26th Annual Conference; 2019

The Society for Redox Biology and Medicine

Inflammatory activation of macrophages plays an important role in tissue damage during chronic inflammatory processes. Toll-like receptor (TLR)-mediated inflammatory activation of macrophages is a well-known model of macrophage activation at chronic inflammation microenvironments. Previously we have shown that the nitrone spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) traps protein radicals and 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 has been crystallized. Our in silico data show that DMPO tightly binds to four specific residues within the BB-loop at the TLR2-TIR domain. Our functional analysis using TLR2.6-expressing HEKs cells showed that DMPO can block zymosan-triggered-TR2-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 development and use of DMPO-derivatives as potential mechanism-based safe antagonists of TLR-triggered inflammation. Supported by: PICT3369/PIP916/PROICOs 100218 and 023418/PUE IMIBIO-SL.