title: TLR4 antagonist FP7 inhibits LPS-induced cytokine production and glycolytic reprogramming in dendritic cells, and protects mice from lethal influenza infection.
abstract: Dysregulated Toll-like receptor (TLR)-4 activation is involved in acute systemic sepsis, chronic inflammatory diseases, such as atherosclerosis and diabetes, and in viral infections, such as influenza infection. Thus, therapeutic control of the TLR4 signalling pathway is of major interest. Here we tested the activity of the small-molecule synthetic TLR4 antagonist, FP7, in vitro on human monocytes and monocyte-derived dendritic cells (DCs) and in vivo during influenza virus infection of mice. Our results indicate that FP7 antagonized the secretion of proinflammatory cytokines (IL-6, IL-8, and MIP-1β) by monocytes and DCs (IC50< 1 μM) and prevented DC maturation upon TLR4 activation by ultrapure lipopolysaccharide (LPS). FP7 selectively blocked TLR4 stimulation, but not TLR1/2, TLR2/6, or TLR3 activation. TLR4 stimulation of human DCs resulted in increased glycolytic activity that was also antagonized by FP7. FP7 protected mice from influenza virus-induced lethality and reduced both proinflammatory cytokine gene expression in the lungs and acute lung injury (ALI). Therefore, FP7 can antagonize TLR4 activation in vitro and protect mice from severe influenza infection, most likely by reducing TLR4-dependent cytokine storm mediated by damage-associated molecular patterns (DAMPs) like HMGB1.
authors.affiliation: CIRI, International Center for Infectiology Research, Université de Lyon, Lyon, France.|Inserm, U1111, Lyon, France.|Ecole Normale Supérieure de Lyon, Lyon, France.|Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France.|CNRS, UMR5308, Lyon, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Perrin-Cocon
authors.affiliation: CIRI, International Center for Infectiology Research, Université de Lyon, Lyon, France.|Inserm, U1111, Lyon, France.|Ecole Normale Supérieure de Lyon, Lyon, France.|Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France.|CNRS, UMR5308, Lyon, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Aublin-Gex
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza, 2, 20126 Milano, Italy.
authors.forename: Stefania E
authors.initials: SE
authors.lastname: Sestito
authors.affiliation: Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Kari Ann
authors.initials: KA
authors.lastname: Shirey
authors.affiliation: Sigmovir Biosystems Inc., Rockville, MD, USA.
authors.forename: Mira C
authors.initials: MC
authors.lastname: Patel
authors.affiliation: CIRI, International Center for Infectiology Research, Université de Lyon, Lyon, France.|Inserm, U1111, Lyon, France.|Ecole Normale Supérieure de Lyon, Lyon, France.|Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France.|CNRS, UMR5308, Lyon, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: André
authors.affiliation: Sigmovir Biosystems Inc., Rockville, MD, USA.
authors.forename: Jorge C
authors.initials: JC
authors.lastname: Blanco
authors.affiliation: Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, Maryland 21201, USA.
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Vogel
authors.affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza, 2, 20126 Milano, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Peri
authors.affiliation: CIRI, International Center for Infectiology Research, Université de Lyon, Lyon, France.|Inserm, U1111, Lyon, France.|Ecole Normale Supérieure de Lyon, Lyon, France.|Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France.|CNRS, UMR5308, Lyon, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Lotteau
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D018836:Inflammation Mediators; D009980:Influenza A virus / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology*; D008297:Male; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009005:Monosaccharides / Q000494:pharmacology; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality / Q000821:virology; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors*; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D009005:Monosaccharides; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D005947:Glucose