NK cell-derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS

Despite increasing recognition of the importance of GM-CSF in autoimmune disease, it remains unclear how GM-CSF is regulated at sites of tissue inflammation. Using GM-CSF fate reporter mice, we show that synovial NK cells produce GM-CSF in autoantibody-mediated inflammatory arthritis. Synovial NK ce...

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Bibliographic Details
Published in:The Journal of experimental medicine 2020-05, Vol.217 (5)
Main Authors: Louis, Cynthia, Souza-Fonseca-Guimaraes, Fernando, Yang, Yuyan, D'Silva, Damian, Kratina, Tobias, Dagley, Laura, Hediyeh-Zadeh, Soroor, Rautela, Jai, Masters, Seth Lucian, Davis, Melissa J, Babon, Jeffrey J, Ciric, Bogoljub, Vivier, Eric, Alexander, Warren S, Huntington, Nicholas D, Wicks, Ian P
Format: Article
Language:English
Subjects:
Animals
Arthritis, Rheumatoid - immunology
Arthritis, Rheumatoid - pathology
Autoantibodies
Autoimmunity
Female
Granulocyte-Macrophage Colony-Stimulating Factor - metabolism
Human health and pathology
Humans
Immunology
Inflammation - immunology
Inflammation - pathology
Innate immunity
Innate Immunity and Inflammation
Interleukin-18 - metabolism
Janus Kinase 2 - metabolism
Killer Cells, Natural - metabolism
Life Sciences
Male
Mice, Inbred C57BL
Myeloid Cells - metabolism
Neutrophils - metabolism
Rhumatology and musculoskeletal system
Signal Transduction
STAT5 Transcription Factor - metabolism
Suppressor of Cytokine Signaling Proteins - metabolism
Synovial Fluid - metabolism
Synovial Membrane - metabolism
Synovial Membrane - pathology
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Summary:Despite increasing recognition of the importance of GM-CSF in autoimmune disease, it remains unclear how GM-CSF is regulated at sites of tissue inflammation. Using GM-CSF fate reporter mice, we show that synovial NK cells produce GM-CSF in autoantibody-mediated inflammatory arthritis. Synovial NK cells promote a neutrophilic inflammatory cell infiltrate, and persistent arthritis, via GM-CSF production, as deletion of NK cells, or specific ablation of GM-CSF production in NK cells, abrogated disease. Synovial NK cell production of GM-CSF is IL-18-dependent. Furthermore, we show that cytokine-inducible SH2-containing protein (CIS) is crucial in limiting GM-CSF signaling not only during inflammatory arthritis but also in experimental allergic encephalomyelitis (EAE), a murine model of multiple sclerosis. Thus, a cellular cascade of synovial macrophages, NK cells, and neutrophils mediates persistent joint inflammation via production of IL-18 and GM-CSF. Endogenous CIS provides a key brake on signaling through the GM-CSF receptor. These findings shed new light on GM-CSF biology in sterile tissue inflammation and identify several potential therapeutic targets.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.20191421