title: Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8.
abstract: Dendritic cell (DC) responses to extracellular self-DNA and self-RNA are prevented by the endosomal seclusion of nucleic acid-recognizing Toll-like receptors (TLRs). In psoriasis, however, plasmacytoid DCs (pDCs) sense self-DNA that is transported to endosomal TLR9 upon forming a complex with the antimicrobial peptide LL37. Whether LL37 also interacts with extracellular self-RNA and how this may contribute to DC activation in psoriasis is not known. Here, we report that LL37 can bind self-RNA released by dying cells, protect it from extracellular degradation, and transport it into endosomal compartments of DCs. In pDC, self-RNA-LL37 complexes activate TLR7 and, like self-DNA-LL37 complexes, trigger the secretion of IFN-alpha without inducing maturation or the production of IL-6 and TNF-alpha. In contrast to self-DNA-LL37 complexes, self-RNA-LL37 complexes also trigger the activation of classical myeloid DCs (mDCs). This occurs through TLR8 and leads to the production of TNF-alpha and IL-6, and the differentiation of mDCs into mature DCs. We also found that self-RNA-LL37 complexes are present in psoriatic skin lesions and are associated with mature mDCs in vivo. Our results demonstrate that the cationic antimicrobial peptide LL37 converts self-RNA into a trigger of TLR7 and TLR8 in human DCs, and provide new insights into the mechanism that drives the auto-inflammatory responses in psoriasis.
authors.affiliation: Department of Immunology, The University of Texas M.D. Anderson Cancer Center, TX 77030, USA.
authors.forename: Dipyaman
authors.initials: D
authors.lastname: Ganguly
authors.forename: Georgios
authors.initials: G
authors.lastname: Chamilos
authors.forename: Roberto
authors.initials: R
authors.lastname: Lande
authors.forename: Josh
authors.initials: J
authors.lastname: Gregorio
authors.forename: Stephan
authors.initials: S
authors.lastname: Meller
authors.forename: Valeria
authors.initials: V
authors.lastname: Facchinetti
authors.forename: Bernhard
authors.initials: B
authors.lastname: Homey
authors.forename: Franck J
authors.initials: FJ
authors.lastname: Barrat
authors.forename: Tomasz
authors.initials: T
authors.lastname: Zal
authors.forename: Michel
authors.initials: M
authors.lastname: Gilliet
mesh_terms: D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D054804:Cathelicidins; D003713:Dendritic Cells / Q000276:immunology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008156:Luciferases; D046911:Macromolecular Substances / Q000276:immunology / Q000378:metabolism*; D008969:Molecular Sequence Data; D011565:Psoriasis / Q000276:immunology*; D012313:RNA / Q000276:immunology / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000276:immunology / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000276:immunology / Q000378:metabolism*
chemical_list: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D046911:Macromolecular Substances; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D012313:RNA; D008156:Luciferases
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