1. Induction of TLR4/TLR2 Interaction and Heterodimer Formation by Low Endotoxic Atypical LPS.
- Author
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Francisco S, Billod JM, Merino J, Punzón C, Gallego A, Arranz A, Martin-Santamaria S, and Fresno M
- Subjects
- Animals, Cell Line, HEK293 Cells, Humans, Immunity, Innate drug effects, Inflammation metabolism, Lipid A pharmacology, Mice, Inbred C57BL, Mice, Knockout, Molecular Docking Simulation, Mice, Endotoxins pharmacology, Lipopolysaccharides pharmacology, Toll-Like Receptor 2 metabolism, Toll-Like Receptor 4 metabolism
- Abstract
The Toll-like receptor 4 (TLR4)/myeloid differentiation protein-2 (MD-2) complex is considered the major receptor of the innate immune system to recognize lipopolysaccharides (LPSs). However, some atypical LPSs with different lipid A and core saccharide moiety structures and compositions than the well-studied enterobacterial LPSs can induce a TLR2-dependent response in innate immune cells. Ochrobactrum intermedium , an opportunistic pathogen, presents an atypical LPS. In this study, we found that O. intermedium LPS exhibits a weak inflammatory activity compared to Escherichia coli LPS and, more importantly, is a specific TLR4/TLR2 agonist, able to signal through both receptors. Molecular docking analysis of O. intermedium LPS predicts a favorable formation of a TLR2/TLR4/MD-2 heterodimer complex, which was experimentally confirmed by fluorescence resonance energy transfer (FRET) in cells. Interestingly, the core saccharide plays an important role in this interaction. This study reveals for the first time TLR4/TLR2 heterodimerization that is induced by atypical LPS and may help to escape from recognition by the innate immune system., Competing Interests: Authors CP, SF and JM were employed by company Diomune SL. Author MF was an advisor of company Diomune SL. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Francisco, Billod, Merino, Punzón, Gallego, Arranz, Martin-Santamaria and Fresno.)
- Published
- 2022
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