title: Synthetic high-density lipoprotein-like nanoparticles potently inhibit cell signaling and production of inflammatory mediators induced by lipopolysaccharide binding Toll-like receptor 4.
abstract: Toll-like receptor 4 (TLR4) plays a critical role in the innate immune system. Stimulation of TLR4 occurs upon binding lipopolysaccharide (LPS), a component of Gram-negative bacterial cell walls. Due to the potency of the induced inflammatory response, there is a growing interest in agents that can most proximally modulate this LPS/TLR4 interaction to prevent downstream cell signaling events and the production of inflammatory mediators. Building on the natural ability of human high-density lipoprotein (HDL) to bind LPS, we synthesized a suite of HDL-like nanoparticles (HDL-like NP). We identified one HDL-like NP that was particularly effective at decreasing TLR4 signaling caused by addition of purified LPS or Gram-negative bacteria to model human cell lines or primary human peripheral blood cells. The HDL-like NP functioned to inhibit TLR4-dependent inflammatory response to LPS derived from multiple bacterial species. Mechanistically, data show that the NP mainly functions by scavenging and neutralizing the LPS toxin. Taken together, HDL-like NPs constitute a powerful endotoxin scavenger with the potential to significantly reduce LPS-mediated inflammation.
authors.affiliation: Feinberg School of Medicine, Department of Urology, Northwestern University, Tarry 16-703, 303 E. Chicago Ave, Chicago, IL 60611, USA; Simpson Querrey Institute for BioNanotechnology, Northwestern University, 303 E. Superior St, Chicago, IL 60611, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Foit
authors.affiliation: Feinberg School of Medicine, Department of Urology, Northwestern University, Tarry 16-703, 303 E. Chicago Ave, Chicago, IL 60611, USA; Simpson Querrey Institute for BioNanotechnology, Northwestern University, 303 E. Superior St, Chicago, IL 60611, USA; International Institute for Nanotechnology (IIN), 2145 Sheridan Road, Evanston, IL 60208, USA; Robert H Lurie Comprehensive Cancer Center (RHLCCC), Northwestern University, Feinberg School of Medicine, 303 E Superior, Chicago, IL 60611, USA. Electronic address: cthaxton003@northwestern.edu.
authors.forename: C Shad
authors.initials: CS
authors.lastname: Thaxton
mesh_terms: D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000276:immunology; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000276:immunology; D016905:Gram-Negative Bacterial Infections / Q000276:immunology / Q000382:microbiology; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000276:immunology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000276:immunology; D008075:Lipoproteins, HDL / Q000737:chemistry* / Q000494:pharmacology*; D053758:Nanoparticles / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008075:Lipoproteins, HDL; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4
keywords: Endotoxin; High-density lipoprotein-like nanoparticle; Inflammatory response; Lipopolysaccharide; Toll-like receptor 4