title: Transcriptome assessment reveals a dominant role for TLR4 in the activation of human monocytes by the alarmin MRP8.
abstract: The alarmins myeloid-related protein (MRP)8 and MRP14 are the most prevalent cytoplasmic proteins in phagocytes. When released from activated or necrotic phagocytes, extracellular MRP8/MRP14 promote inflammation in many diseases, including infections, allergies, autoimmune diseases, rheumatoid arthritis, and inflammatory bowel disease. The involvement of TLR4 and the multiligand receptor for advanced glycation end products as receptors during MRP8-mediated effects on inflammation remains controversial. By comparative bioinformatic analysis of genome-wide response patterns of human monocytes to MRP8, endotoxins, and various cytokines, we have developed a model in which TLR4 is the dominant receptor for MRP8-mediated phagocyte activation. The relevance of the TLR4 signaling pathway was experimentally validated using human and murine models of TLR4- and receptor for advanced glycation end products-dependent signaling. Furthermore, our systems biology approach has uncovered an antiapoptotic role for MRP8 in monocytes, which was corroborated by independent functional experiments. Our data confirm the primary importance of the TLR4/MRP8 axis in the activation of human monocytes, representing a novel and attractive target for modulation of the overwhelming innate immune response.
authors.affiliation: Institute of Immunology, University of Muenster, 48149 Muenster, Germany;
authors.forename: Selina K
authors.initials: SK
authors.lastname: Fassl
authors.affiliation: Institute of Immunology, University of Muenster, 48149 Muenster, Germany; Interdisciplinary Center for Clinical Research, University of Muenster, 48149 Muenster, Germany;
authors.forename: Judith
authors.initials: J
authors.lastname: Austermann
authors.affiliation: Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
authors.forename: Olympia
authors.initials: O
authors.lastname: Papantonopoulou
authors.affiliation: Genetic Epidemiology of Vascular Disorders, University of Muenster, 48149 Muenster, Germany;
authors.forename: Mona
authors.initials: M
authors.lastname: Riemenschneider
authors.affiliation: Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
authors.forename: Jia
authors.initials: J
authors.lastname: Xue
authors.affiliation: Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany;
authors.forename: Damien
authors.initials: D
authors.lastname: Bertheloot
authors.affiliation: Institute of Immunology, University of Muenster, 48149 Muenster, Germany;
authors.forename: Nicole
authors.initials: N
authors.lastname: Freise
authors.affiliation: Institute of Immunology, University of Muenster, 48149 Muenster, Germany;
authors.forename: Christoph
authors.initials: C
authors.lastname: Spiekermann
authors.affiliation: Genetic Epidemiology of Vascular Disorders, University of Muenster, 48149 Muenster, Germany;
authors.forename: Anika
authors.initials: A
authors.lastname: Witten
authors.affiliation: Clinic for Pediatric Pneumology and Neonatology, Hannover Medical School, 30625 Hannover, Germany;
authors.forename: Dorothee
authors.initials: D
authors.lastname: Viemann
authors.affiliation: Institute for Medical Microbiology and Hygiene, University Medical Center, 79104 Freiburg, Germany;
authors.forename: Susanne
authors.initials: S
authors.lastname: Kirschnek
authors.affiliation: Genetic Epidemiology of Vascular Disorders, University of Muenster, 48149 Muenster, Germany;
authors.forename: Monika
authors.initials: M
authors.lastname: Stoll
authors.affiliation: Institute of Innate Immunity, University Hospital, University of Bonn, 53127 Bonn, Germany; Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605; and German Center for Neurodegenerative Diseases, 53117 Bonn, Germany.
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.affiliation: Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany;
authors.forename: Joachim L
authors.initials: JL
authors.lastname: Schultze
authors.affiliation: Institute of Immunology, University of Muenster, 48149 Muenster, Germany; Interdisciplinary Center for Clinical Research, University of Muenster, 48149 Muenster, Germany;
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.affiliation: Institute of Immunology, University of Muenster, 48149 Muenster, Germany; Interdisciplinary Center for Clinical Research, University of Muenster, 48149 Muenster, Germany; vogl@uni-muenster.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogl
mesh_terms: D000818:Animals; D040501:Calgranulin A / Q000276:immunology*; D040502:Calgranulin B / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D007249:Inflammation / Q000276:immunology; D008297:Male; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology*
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4