Dysregulation of the Cytokine GM-CSF Induces Spontaneous Phagocyte Invasion and Immunopathology in the Central Nervous System
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...
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| Veröffentlicht in: | Immunity (Cambridge, Mass.) Jg. 46; H. 2; S. 245 |
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21.02.2017
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| 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. |
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| AbstractList | 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. 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.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. |
| Author | Komuczki, Juliana Pelczar, Pawel Hermann, Mario Schreiner, Bettina Mair, Florian Spath, Sabine Becher, Burkhard |
| Author_xml | – sequence: 1 givenname: Sabine surname: Spath fullname: Spath, Sabine organization: Institute of Experimental Immunology, Inflammation Research, University of Zurich, 8057 Zurich, Switzerland – sequence: 2 givenname: Juliana surname: Komuczki fullname: Komuczki, Juliana organization: Institute of Experimental Immunology, Inflammation Research, University of Zurich, 8057 Zurich, Switzerland – sequence: 3 givenname: Mario surname: Hermann fullname: Hermann, Mario organization: Institute of Laboratory Animal Science, University of Zurich, 8091 Zurich, Switzerland; Institute of Neuropathology, University Hospital Zurich, 8091 Zurich, Switzerland – sequence: 4 givenname: Pawel surname: Pelczar fullname: Pelczar, Pawel organization: Institute of Laboratory Animal Science, University of Zurich, 8091 Zurich, Switzerland – sequence: 5 givenname: Florian surname: Mair fullname: Mair, Florian organization: Institute of Experimental Immunology, Inflammation Research, University of Zurich, 8057 Zurich, Switzerland – sequence: 6 givenname: Bettina surname: Schreiner fullname: Schreiner, Bettina email: schreiner@immunology.uzh.ch organization: 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 – sequence: 7 givenname: Burkhard surname: Becher fullname: Becher, Burkhard email: becher@immunology.uzh.ch organization: Institute of Experimental Immunology, Inflammation Research, University of Zurich, 8057 Zurich, Switzerland. Electronic address: becher@immunology.uzh.ch |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/28228281$$D View this record in MEDLINE/PubMed |
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| Keywords | moDCs myeloid cells phagocytes GM-CSF inflammatory monocytes multiple sclerosis reactive oxygen species cytokines brain CNS inflammation histiocytosis |
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| SubjectTerms | Animals Central Nervous System - immunology Central Nervous System - pathology Flow Cytometry Granulocyte-Macrophage Colony-Stimulating Factor - immunology Immunohistochemistry Mice Mice, Inbred C57BL Mice, Transgenic Models, Animal Phagocytes - immunology Polymerase Chain Reaction |
| Title | Dysregulation of the Cytokine GM-CSF Induces Spontaneous Phagocyte Invasion and Immunopathology in the Central Nervous System |
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