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Glucosylceramide modifies the LPS-induced inflammatory response in macrophages and the orientation of the LPS/TLR4 complex in silico

Journal article
Authors E. Mobarak
Liliana Håversen
M. Manna
Mikael Rutberg
Malin Levin
Rosie Perkins
T. Rog
I. Vattulainen
Jan Borén
Published in Scientific Reports
Volume 8
ISSN 2045-2322
Publication year 2018
Published at Wallenberg Laboratory
Institute of Medicine, Department of Molecular and Clinical Medicine
Language en
Links dx.doi.org/10.1038/s41598-018-31926...
Keywords toll-like receptors, atom force-field, molecular-dynamics simulations, human atherosclerotic plaque, tlr4-md-2 complex, swiss-model, lipid, rafts, atomistic simulations, signal-transduction, structural basis, Science & Technology - Other Topics, lch j, 1957, journal of biological chemistry, v226, p497
Subject categories Cell Biology

Abstract

Toll-like receptor 4 (TLR4) is activated by bacterial lipopolysaccharide (LPS), which drives the production of proinflammatory cytokines. Earlier studies have indicated that cholesterol-and glycosphingolipid-rich subregions of the plasma membrane (lipid domains) are important for TLR4-mediated signaling. We report that inhibition of glucosylceramide (GluCer) synthase, which resulted in decreased concentrations of the glycosphingolipid GluCer in lipid domains, reduced the LPS-induced inflammatory response in both mouse and human macrophages. Atomistic molecular dynamics simulations of the TLR4 dimer complex (with and without LPS in its MD-2 binding pockets) in membranes (in the presence and absence of GluCer) showed that: (1) LPS induced a tilted orientation of TLR4 and increased dimer integrity; (2) GluCer did not affect the integrity of the LPS/TLR4 dimer but reduced the LPS-induced tilt; and (3) GluCer increased electrostatic interactions between the membrane and the TLR4 extracellular domain, which could potentially modulate the tilt. We also showed that GCS inhibition reduced the interaction between TLR4 and the intracellular adaptor protein Mal. We conclude that the GluCer-induced effects on LPS/TLR4 orientation may influence the signaling capabilities of the LPS/TLR4 complex by affecting its interaction with downstream signaling proteins.

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