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Dysregulation of the Cytokine GM-CSF Induces Spontaneous Phagocyte Invasion and Immunopathology in the Central Nervous System


Spath, Sabine; Komuczki, Juliana; Hermann, Mario; Pelczar, Pawel; Mair, Florian; Schreiner, Bettina; Becher, Burkhard (2017). Dysregulation of the Cytokine GM-CSF Induces Spontaneous Phagocyte Invasion and Immunopathology in the Central Nervous System. Immunity, 46(2):245-260.

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.

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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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
04 Faculty of Medicine > Institute of Experimental Immunology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:21 February 2017
Deposited On:05 Oct 2017 13:25
Last Modified:19 Aug 2018 10:30
Publisher:Cell Press (Elsevier)
ISSN:1074-7613
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.immuni.2017.01.007
PubMed ID:28228281
Project Information:
  • : FunderSNSF
  • : Grant IDCRSII3_136203
  • : Project TitleThe interplay between innate and adaptive tumor-specific immune responses induced through local tumor therapy in skin cancer
  • : FunderSNSF
  • : Grant ID316030_150768
  • : Project TitleThe use of Mass-cytometry in multi-parameter immune cell analysis
  • : FunderSNSF
  • : Grant ID310030_146130
  • : Project TitleThe role of the NF?B-inducing kinase NIK in the development and function of cellular immunity
  • : FunderFP7
  • : Grant ID279017
  • : Project TitleTARGETBRAIN - Targeting Brain Inflammation For Improved Functional Recovery in Acute Neurodegenerative Disorders
  • : FunderFP7
  • : Grant ID316722
  • : Project TitleNEUROKINE - Initial Training Network for Neurogical disorders orchestrated by cytoKines
  • : FunderFP7
  • : Grant ID602239
  • : Project TitleATECT - Advanced T-cell Engineered for Cancer Therapy

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