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 - HAL Accéder directement au contenu
Article dans une revue Biochimica et Biophysica Acta - Molecular Basis of Disease Année : 2019

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

Résumé

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.

Domaines

Immunologie
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Dates et versions

hal-02328201, version 1 (23-10-2019)

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Marcos Muñoz, Lucas J Gutierrez, Sandrine Delignat, Jules Russick, Sandra Gomez, et al.. 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. Biochimica et Biophysica Acta - Molecular Basis of Disease, 2019, ⟨10.1016/j.bbadis.2019.01.005⟩. ⟨hal-02328201⟩
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