NK cell-derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS
AuthorLouis, C; Souza-Fonseca-Guimaraes, F; Yang, Y; D'Silva, D; Kratina, T; Dagley, L; Hediyeh-Zadeh, S; Rautela, J; Masters, SL; Davis, MJ; ...
Source TitleJournal of Experimental Medicine
PublisherROCKEFELLER UNIV PRESS
University of Melbourne Author/sBabon, Jeffrey; Alexander, Warren; Huntington, Nicholas; Davis, Melissa; Masters, Seth; Rautela, Jai; Louis, Cynthia; Wicks, Ian; Dagley, Laura; Fonseca Guimaraes, Fernando
AffiliationMedical Biology (W.E.H.I.)
Medicine and Radiology
Document TypeJournal Article
CitationsLouis, C., Souza-Fonseca-Guimaraes, F., Yang, Y., D'Silva, D., Kratina, T., Dagley, L., Hediyeh-Zadeh, S., Rautela, J., Masters, S. L., Davis, M. J., Babon, J. J., Ciric, B., Vivier, E., Alexander, W. S., Huntington, N. D. & Wicks, I. P. (2020). NK cell-derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS. JOURNAL OF EXPERIMENTAL MEDICINE, 217 (5), https://doi.org/10.1084/jem.20191421.
Access StatusOpen Access
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.
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