title: Alarmins MRP8 and MRP14 induce stress tolerance in phagocytes under sterile inflammatory conditions.
abstract: Hyporesponsiveness by phagocytes is a well-known phenomenon in sepsis that is frequently induced by low-dose endotoxin stimulation of Toll-like receptor 4 (TLR4) but can also be found under sterile inflammatory conditions. We now demonstrate that the endogenous alarmins MRP8 and MRP14 induce phagocyte hyporesponsiveness via chromatin modifications in a TLR4-dependent manner that results in enhanced survival to septic shock in mice. During sterile inflammation, polytrauma and burn trauma patients initially present with high serum concentrations of myeloid-related proteins (MRPs). Human neonatal phagocytes are primed for hyporesponsiveness by increased peripartal MRP concentrations, which was confirmed in murine neonatal endotoxinemia in wild-type and MRP14(-/-) mice. Our data therefore indicate that alarmin-triggered phagocyte tolerance represents a regulatory mechanism for the susceptibility of neonates during systemic infections and sterile inflammation.
authors.affiliation: Institute of Immunology, University of Münster, 48149 Münster, Germany; Interdisciplinary Centre for Clinical Research, University of Münster, 48149 Münster, Germany. Electronic address: judithaustermann@gmx.de.
authors.forename: Judith
authors.initials: J
authors.lastname: Austermann
authors.affiliation: Department of Pediatric Pneumology, Allergy and Neonatology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Friesenhagen
authors.affiliation: Institute of Immunology, University of Münster, 48149 Münster, Germany.
authors.forename: Selina Kathleen
authors.initials: SK
authors.lastname: Fassl
authors.forename: Beatrix
authors.initials: B
authors.lastname: Petersen
authors.affiliation: Institute of Immunology, University of Münster, 48149 Münster, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Ortkras
authors.affiliation: Department of Pediatric Pneumology, Allergy and Neonatology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Burgmann
authors.affiliation: Institute of Immunology, University of Münster, 48149 Münster, Germany.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Barczyk-Kahlert
authors.affiliation: Department of Surgery and Clinical Study Center, Ludwig-Maximilian University, 81377 Munich, Germany.
authors.forename: Eugen
authors.initials: E
authors.lastname: Faist
authors.affiliation: Department of Surgery and Clinical Study Center, Ludwig-Maximilian University, 81377 Munich, Germany.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Zedler
authors.affiliation: Department of Pediatric Pneumology, Allergy and Neonatology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Pirr
authors.affiliation: Department of Molecular Haematology and Oncology, Internal Medicine Clinic IV, University Medical Center Halle (Saale), 06120 Halle, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Rohde
authors.affiliation: Department of Molecular Haematology and Oncology, Internal Medicine Clinic IV, University Medical Center Halle (Saale), 06120 Halle, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine Hannover, 30625 Hannover, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: von Köckritz-Blickwede
authors.affiliation: Department of Gynaecology and Prenatal Medicine, Medical School Hannover, 30625 Hannover, Germany.
authors.forename: Constantin S
authors.initials: CS
authors.lastname: von Kaisenberg
authors.affiliation: Surgical Research, Department of Trauma Surgery, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany.
authors.forename: Stefanie B
authors.initials: SB
authors.lastname: Flohé
authors.affiliation: Genomics and Immunoregulation, LIMES-Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ulas
authors.affiliation: Genomics and Immunoregulation, LIMES-Institute, University of Bonn, 53115 Bonn, Germany.
authors.forename: Joachim L
authors.initials: JL
authors.lastname: Schultze
authors.affiliation: Institute of Immunology, University of Münster, 48149 Münster, Germany; Interdisciplinary Centre for Clinical Research, University of Münster, 48149 Münster, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.affiliation: Institute of Immunology, University of Münster, 48149 Münster, Germany; Interdisciplinary Centre for Clinical Research, University of Münster, 48149 Münster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogl
authors.affiliation: Department of Pediatric Pneumology, Allergy and Neonatology, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Viemann
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002056:Burns / Q000276:immunology / Q000378:metabolism; D040501:Calgranulin A / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D040502:Calgranulin B / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007249:Inflammation / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D010586:Phagocytes / Q000276:immunology / Q000378:metabolism*; D012772:Shock, Septic / Q000276:immunology / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; D016328:NF-kappa B