title: Targeting the TLR co-receptor CD14 with TLR2-derived peptides modulates immune responses to pathogens.
abstract: Dysregulation of Toll-like receptor (TLR) responses to pathogens can lead to pathological inflammation or to immune hyporesponsiveness and susceptibility to infections, and may affect adaptive immune responses. TLRs are therefore attractive therapeutic targets. We assessed the potential of the TLR co-receptor CD14 as a target for therapeutics by investigating the magnitude of its influence on TLR responses. We studied the interaction of CD14 with TLR2 by conducting peptide screening and site-directed mutagenesis analysis and found TLR2 leucine-rich repeats 5, 9, 15, and 20 involved in interaction with CD14. Peptides representing these regions interacted with CD14 and enhanced TLR2- and TLR4-mediated proinflammatory responses to bacterial pathogens in vitro. Notably, the peptides' immune boosting capacity helped to rescue proinflammatory responses of immunosuppressed sepsis patients ex vivo. In vivo, peptide treatment increased phagocyte recruitment and accelerated bacterial clearance in murine models of Gram-negative and Gram-positive bacterial peritonitis. Up-modulating CD14's co-receptor activity with TLR2-derived peptides also enhanced antigen-induced dendritic cell (DC) maturation and interleukin-2 production and, most notably, differentially affected DC cytokine profile upon antigen stimulation, promoting a T helper 1-skewed adaptive immune response. Biochemical, cell imaging, and molecular docking studies showed that peptide binding to CD14 accelerates microbial ligand transfer from CD14 to TLR2, resulting in increased and sustained ligand occupancy of TLR2 and receptor clustering for signaling. These findings reveal the influence that CD14 exerts on TLR activities and describe a potential therapeutic strategy to amplify responses to different pathogens mediated by different TLRs by targeting the common TLR co-receptor, CD14.
authors.affiliation: Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Anne-Catherine
authors.initials: AC
authors.lastname: Raby
authors.forename: Benjamin
authors.initials: B
authors.lastname: Holst
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Le Bouder
authors.forename: Constantino
authors.initials: C
authors.lastname: Diaz
authors.forename: Edgardo
authors.initials: E
authors.lastname: Ferran
authors.forename: Laurence
authors.initials: L
authors.lastname: Conraux
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Guillemot
authors.forename: Barbara
authors.initials: B
authors.lastname: Coles
authors.forename: Ann
authors.initials: A
authors.lastname: Kift-Morgan
authors.forename: Chantal S
authors.initials: CS
authors.lastname: Colmont
authors.forename: Tamas
authors.initials: T
authors.lastname: Szakmany
authors.forename: Pascual
authors.initials: P
authors.lastname: Ferrara
authors.forename: Judith E
authors.initials: JE
authors.lastname: Hall
authors.forename: Nicholas
authors.initials: N
authors.lastname: Topley
authors.forename: Mario O
authors.initials: MO
authors.lastname: Labéta
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001419:Bacteria / Q000187:drug effects / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D007109:Immunity / Q000187:drug effects / Q000276:immunology*; D007165:Immunosuppression Therapy; D007249:Inflammation / Q000150:complications / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D000090263:Leucine-Rich Repeat Proteins; D008024:Ligands; D018950:Lipopolysaccharide Receptors / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008074:Lipoproteins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D050296:Microbial Viability / Q000187:drug effects; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D010538:Peritonitis / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D010586:Phagocytes / Q000166:cytology / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011506:Proteins / Q000276:immunology; D018805:Sepsis / Q000150:complications / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000737:chemistry*
chemical_list: D016207:Cytokines; D000090263:Leucine-Rich Repeat Proteins; D008024:Ligands; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008074:Lipoproteins; D010455:Peptides; D011506:Proteins; D051195:Toll-Like Receptor 2; C061108:N-palmitoyl-S-(2,3-bis(palmitoyloxy)propyl)cysteinyl-seryl-lysyl-lysyl-lysyl-lysine