title: Activation-dependent cell death of human monocytes is a novel mechanism of fine-tuning inflammation and autoimmunity.
abstract: In patients with juvenile idiopathic arthritis (JIA), increased release of IFN-γ and GM-CSF in cells infiltrating synovial tissue can be a potent driver of monocyte activation. Given the fundamental role of monocyte activation in remodeling the early phases of inflammatory responses, here we analyze the GM-CSF/IFN-γ induced activity of human monocytes in such a situation in vitro and in vivo. Monocytes from healthy donors were isolated and stimulated with GM-CSF ± IFN-γ. Monocyte activation and death were analyzed by flow cytometry, immunofluorescence microscopy, ELISA, and qPCR. T-cell GM-CSF/IFN-γ expression and monocyte function were determined in synovial fluid and peripheral blood from 15 patients with active JIA and 21 healthy controls. Simultaneous treatment with GM-CSF and IFN-γ induces cell death of monocytes. This cell death is partly cathepsin B-associated and has morphological characteristics of necrosis. Monocytes responding to costimulation with strong proinflammatory activities are consequently eliminated. Monocytes surviving this form of hyperactivation retain normal cytokine production. Cathepsin B activity is increased in monocytes isolated from synovial fluid from patients with active arthritis. Our data suggest GM-CSF/IFN-γ induced cell death of monocytes as a novel mechanism to eliminate overactivated monocytes, thereby potentially balancing inflammation and autoimmunity in JIA.
authors.affiliation: Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany.|Department of Pediatrics, University Hospital Rostock, Rostock, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Däbritz
authors.affiliation: Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany.
authors.forename: Toni
authors.initials: T
authors.lastname: Weinhage
authors.affiliation: Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Varga
authors.affiliation: Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Wirth
authors.affiliation: Department of Dermatology, University Hospital Münster, Münster, Germany.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Ehrchen
authors.affiliation: Institute of Immunology, University Hospital Münster, Münster, Germany.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Barczyk-Kahlert
authors.affiliation: Institute of Immunology, University Hospital Münster, Münster, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.affiliation: St. Josef-Stift, Sendenhorst, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schwarz
authors.affiliation: Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Foell
mesh_terms: D000293:Adolescent; D001171:Arthritis, Juvenile / Q000276:immunology*; D015551:Autoimmunity; D016022:Case-Control Studies; D002401:Cathepsin B / Q000378:metabolism; D016923:Cell Death; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008297:Male; D009000:Monocytes / Q000276:immunology*; D013582:Synovial Fluid
chemical_list: D016207:Cytokines; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002401:Cathepsin B
keywords: Arthritis · Autoimmunity · Caspase · Host defense ·Immune activation · Immune response