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Toll-like receptor 2 promiscuity is responsible for the immunostimulatory activity of nucleic acid nanocarriers
Abstract : Lipopolyamines (LPAs) are cationic lipids; they interact spontaneouslywith nucleic acids to formlipoplexes used for gene delivery. The main hurdle to using lipoplexes in gene therapy lies in their immunostimulatory properties, so far attributed to the nucleic acid cargo, while cationic lipids were considered as inert to the immune system. Here we demonstrate for the first time that di-C18 LPAs trigger pro-inflammatory responses through Tolllike receptor 2 (TLR2) activation, and this whether they are bound to nucleic acids or not. Molecular docking experiments suggest potential TLR2 binding modes reminiscent of bacterial lipopeptide sensing. The di-C18 LPAs share the ability of burying their lipid chains in the hydrophobic cavity of TLR2 and, in some cases, TLR1, at the vicinity of the dimerization interface; the cationic headgroups form multiple hydrogen bonds, thus crosslinking TLRs into functional complexes. Unravelling the molecular basis of TLR1 and TLR6-driven heterodimerization upon LPA binding underlines the highly collaborative and promiscuous ligand binding mechanism. The prevalence of non-specificmain chain-mediated interactions demonstrates that potentially any saturated LPA currently used or proposed as transfection agent is likely to activate TLR2 during transfection. Hence our study emphasizes the urgent need to test the inflammatory properties of transfection agents and proposes the use of docking analysis as a preliminary screening tool for the synthesis of new non-immunostimulatory nanocarriers. (C) 2017 The Authors. Published by Elsevier B. V. This is an open access article under the CC BY license.
https://hal-cnrs.archives-ouvertes.fr/hal-03292052
Contributor : Colette Orange Connect in order to contact the contributor
Submitted on : Friday, September 10, 2021 - 10:54:16 AM
Last modification on : Tuesday, October 19, 2021 - 12:55:43 PM
Contributor : Colette Orange Connect in order to contact the contributor
Submitted on : Friday, September 10, 2021 - 10:54:16 AM
Last modification on : Tuesday, October 19, 2021 - 12:55:43 PM
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