Research Publications

Back

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


Louis, C; Guimaraes, F; Yang, Y; D'Silva, D; Kratina, T; Dagley, L; Hediyeh-Zadeh, S; Rautela, J; Masters, SL; Davis, MJ; Babon, JJ; Ciric, B; Vivier, E; Alexander, WS; Huntington, ND; Wicks, IP
2020-05-04
Journal of Experimental Medicine
Journal Article
217
5
e20191421
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.
Rockefeller University Press
Inflammation; Advanced Technology and Biology; Bioinformatics; Immunology; Structural Biology; Blood Cells and Blood Cancer
10.1084/jem.20191421
32097462
Refer to article for additional funding acknowledgements
Refer to copyright notice on published article.