title: Dysregulation of the Cytokine GM-CSF Induces Spontaneous Phagocyte Invasion and Immunopathology in the Central Nervous System.
abstract: Chronic inflammatory diseases are influenced by dysregulation of cytokines. Among them, granulocyte macrophage colony stimulating factor (GM-CSF) is crucial for the pathogenic function of T cells in preclinical models of autoimmunity. To study the impact of dysregulated GM-CSF expression in vivo, we generated a transgenic mouse line allowing the induction of GM-CSF expression in mature, peripheral helper T (Th) cells. Antigen-independent GM-CSF release led to the invasion of inflammatory myeloid cells into the central nervous system (CNS), which was accompanied by the spontaneous development of severe neurological deficits. CNS-invading phagocytes produced reactive oxygen species and exhibited a distinct genetic signature compared to myeloid cells invading other organs. We propose that the CNS is particularly vulnerable to the attack of monocyte-derived phagocytes and that the effector functions of GM-CSF-expanded myeloid cells are in turn guided by the tissue microenvironment.
authors.affiliation: Institute of Experimental Immunology, Inflammation Research, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Spath
authors.affiliation: Institute of Experimental Immunology, Inflammation Research, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Juliana
authors.initials: J
authors.lastname: Komuczki
authors.affiliation: Institute of Laboratory Animal Science, University of Zurich, 8091 Zurich, Switzerland; Institute of Neuropathology, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Mario
authors.initials: M
authors.lastname: Hermann
authors.affiliation: Institute of Laboratory Animal Science, University of Zurich, 8091 Zurich, Switzerland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Pelczar
authors.affiliation: Institute of Experimental Immunology, Inflammation Research, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Florian
authors.initials: F
authors.lastname: Mair
authors.affiliation: Institute of Experimental Immunology, Inflammation Research, University of Zurich, 8057 Zurich, Switzerland; Department of Neurology, University Hospital Zurich, 8091 Zurich, Switzerland. Electronic address: schreiner@immunology.uzh.ch.
authors.forename: Bettina
authors.initials: B
authors.lastname: Schreiner
authors.affiliation: Institute of Experimental Immunology, Inflammation Research, University of Zurich, 8057 Zurich, Switzerland. Electronic address: becher@immunology.uzh.ch.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Becher
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000276:immunology* / Q000473:pathology*; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D010586:Phagocytes / Q000276:immunology*; D016133:Polymerase Chain Reaction
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: CNS inflammation; GM-CSF; brain; cytokines; histiocytosis; inflammatory monocytes; moDCs; multiple sclerosis; myeloid cells; phagocytes; reactive oxygen species