title: RAGE Enhances TLR Responses through Binding and Internalization of RNA.
abstract: Nucleic acid recognition is an important mechanism that enables the innate immune system to detect microbial infection and tissue damage. To minimize the recognition of self-derived nucleic acids, all nucleic acid-sensing signaling receptors are sequestered away from the cell surface and are activated in the cytoplasm or in endosomes. Nucleic acid sensing in endosomes relies on members of the TLR family. The receptor for advanced glycation end-products (RAGE) was recently shown to bind DNA at the cell surface, facilitating DNA internalization and subsequent recognition by TLR9. In this article, we show that RAGE binds RNA molecules in a sequence-independent manner and enhances cellular RNA uptake into endosomes. Gain- and loss-of-function studies demonstrate that RAGE increases the sensitivity of all ssRNA-sensing TLRs (TLR7, TLR8, TLR13), suggesting that RAGE is an integral part of the endosomal nucleic acid-sensing system.
authors: Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany.
authors: Damien
authors: 0000-0002-9495-706X
authors: D
authors: Bertheloot
authors: MedImmune LLC, Gaithersburg, MD 20878.
authors: Allison L
authors: AL
authors: Naumovski
authors: Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany.|German Center for Neurodegenerative Diseases, 53117 Bonn, Germany.
authors: Pia
authors: 0000-0002-8568-7168
authors: P
authors: Langhoff
authors: Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany.
authors: Gabor L
authors: 0000-0003-0309-595X
authors: GL
authors: Horvath
authors: School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, China.
authors: Tengchuan
authors: T
authors: Jin
authors: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106.
authors: Tsan Sam
authors: 0000-0001-9688-475X
authors: TS
authors: Xiao
authors: Institute of Molecular Medicine and Experimental Immunology, University of Bonn, 53127 Bonn, Germany.
authors: Natalio
authors: N
authors: Garbi
authors: Idera Pharmaceuticals, Cambridge, MA 02139; and.
authors: Sudhir
authors: 0000-0003-4275-2510
authors: S
authors: Agrawal
authors: MedImmune LLC, Gaithersburg, MD 20878.
authors: Roland
authors: R
authors: Kolbeck
authors: Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany; eicke.latz@uni-bonn.de.|German Center for Neurodegenerative Diseases, 53117 Bonn, Germany.|Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605.
authors: Eicke
authors: E
authors: Latz
mesh_terms: D004247:DNA / Q000235:genetics / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000276:immunology / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology*
chemical_list: D000067759:Receptor for Advanced Glycation End Products; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051193:Toll-Like Receptors; D012313:RNA; D004247:DNA