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

Published in: Journal of Experimental Medicine, 2020, 217 (5), pp.e20191421. ⟨10.1084/jem.20191421⟩

Authors: Cynthia Louis, Fernando Souza-Fonseca-Guimaraes, Yuyan Yang, Damian D’silva, Tobias Kratina, Laura Dagley, Soroor Hediyeh-Zadeh, Jai Rautela, Seth Lucian Masters, Melissa Davis, Jeffrey Babon, Bogoljub Ciric, Eric Vivier, Warren Alexander, Nicholas Huntington, Ian Wicks

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

Link to HAL – hal-04831564

Link to DOI – 10.1084/jem.20191421